Background CT radiation is arguably carcinogenic. Results from single-centre studies, mostly retrospective, have advocated lowering the CT radiation dose for the diagnosis of appendicitis. However, adoption of low-dose CT has been slow. We aimed to assess the effectiveness of low-dose CT compared with standard-dose CT in the diagnosis of appendicitis in adolescents and young adults. Methods We did this pragmatic, multicentre, randomised controlled non-inferiority trial at 20 South Korean teaching hospitals with little experience with low-dose CT. Patients aged 15–44 years with suspected appendicitis were randomly assigned (1:1), via computer-generated random assignments (permuted block sizes of two, four, six, and eight) concealed in sequentially numbered envelopes, to receive low-dose CT (2 mSv) or standard-dose CT (≤8 mSv). Randomisation was stratified by site. Group allocation was concealed from patients, outcome assessors, and adverse event adjudicators; care providers, site pathologists, and data collectors were aware of allocation. The primary endpoint was the negative (unnecessary) appendectomy rate among all appendectomies, with a non-interiority margin of 4·5% for low-dose versus standard-dose CT. Primary analysis was by modified intention to treat, which included all patients who received an appendectomy in the group to which they were assigned. This trial is registered with ClinicalTrials.gov, number NCT01925014. Findings Between Dec 4, 2013, and Aug 18, 2016, we assigned 1535 patients to the low-dose CT group and 1539 patients to the standard-dose CT group. 22 (3·9%) of 559 patients had a negative appendectomy in the low-dose group versus 16 (2·7%) of 601 patients in the standard-dose group (difference 1·3%, 95% CI −0·8 to 3·3; p=0·0022 for the non-inferiority test). We recorded 43 adverse events in 43 (2·8%) of 1535 patients in the low-dose group and 41 adverse events in 40 (2·6%) of 1539 patients in the standard-dose group. One life-threatening adverse event of anaphylaxis caused by an iodinated contrast material occurred in the low-dose group. Interpretation Radiation dose of appendiceal CT for adolescents and young adults can be reduced to 2 mSv without impairing clinical outcomes. In view of the vast number of appendiceal CT examinations done worldwide, use of low-dose CT could prevent a sizeable number of radiation-associated cancers in the future. Funding Korea Health Industry Development Institute, Seoul National University Bundang Hospital, Dasol Life Science, and Bracco Imaging Korea.
Bibliographical noteFunding Information:
Low-dose CT was successfully delivered without impairing clinically important outcomes, despite the limited previous experience with low-dose CT in most of the 20 LOCAT sites. The low-dose and standard-dose groups were similar with regard to negative appendectomy rate (which is an indicator of false-positive diagnosis). The two groups were also similar for endpoints related to false-negative (or delayed) diagnosis, including appendiceal perforation rate, prevalence of perforated appendicitis, interval between CT and appendectomy, hospital stay associated with appendectomy, and diagnostic sensitivity. LOCAT corroborates results from previous studies 7,11,12 advocating the use of low-dose CT in adults. Although the radiation doses varied slightly across these previous studies, the differences between low-dose and standard-dose CT for negative appendectomy rate, appendiceal perforation rate, and diagnostic performance were consistently small, both across the previous studies and between the subgroups in LOCAT. These results can be attributed to the excellent imaging capability of modern CT machines and the inherent simplicity of CT-image interpretation in diagnosing appendicitis, which might offset the loss of image quality in low-dose CT. 7 These results should not be interpreted as an encouragement to increase use of CT by introducing the low-dose technique. A successful reduction of population radiation dose should entail judicious CT use and dose lowering in individual examinations. In this context, stepwise diagnostic protocols 2 limiting CT use to clinically or ultrasonographically equivocal cases are most welcomed, and the protocols should ideally incorporate low-dose CT. Our results were largely consistent across the subgroups stratified by the clinical risk scores for appendicitis, including those with intermediate risk. For CT radiation dose, a vast disparity exists between science and practice. For example, despite ample evidence supporting the use of low-dose CT for renal colic, its uptake during 2011–13 in the USA was limited to 2% of relevant patients. 20 We intended to do a pragmatic trial in acknowledgment of this challenge. With the broad eligibility criteria largely dependent on the judgment of individual care providers, the study results would apply to a broad spectrum of patients. The recruitment of the patients and care providers, choice of target dose for standard-dose CT, details on the CT techniques and interpretations, and all downstream diagnostic and therapeutic procedures followed the usual site practices without using extra resources. Residents made the initial CT reports for 40% of the included patients. With this pragmatic design, we expected that the sites would eventually embed low-dose CT into their usual care through the implementation of the LOCAT protocol. 13 As of May 31, 2017, 14 of the 20 sites had lowered their standard-of-practice dose to 2 mSv. Follow-up investigations are needed as to whether the remaining sites will eventually join this change and how sustainable the low-dose CT practice will be. We adopted the conventional endpoints of negative appendectomy rate and appendiceal perforation rate on the basis that the low-dose and standard-dose CT groups would be balanced in the numbers of appendectomies and confirmed appendicitis cases, which were the denominators of the endpoints. Our data show that this premise might not have been true, which suggests that the two conventional endpoints are not ideal indicators of overall quality of care. 2,21 The potential imbalance might be attributable to a small number of cases of non-perforated incipient appendicitis that were undetected with CT and then resolved without appendectomy. 2,21,22 More cases of incipient appendicitis could have occurred in the low-dose CT group than the standard-dose group because of the restricted capability of low-dose CT to depict subtle inflammation. A similar imbalance was observed in a trial 23 that reported a higher prevalence of appendicitis in an early laparoscopy group than in a watchful-waiting group. Those incipient cases, by being counted as true negatives, might partly explain the counterintuitive results of the higher diagnostic specificity in the low-dose CT group than in the standard-dose group. It would be worthwhile to further explore LOCAT data regarding the use of CT, particularly at low doses, in the triage of patients with uncomplicated appendicitis that would respond to non-surgical treatment. 24 We observed very small between-group differences for the number of negative appendectomies and prevalence of perforated appendicitis among all randomly assigned patients. The point estimates imply that use of low-dose instead of standard-dose CT in an estimated 1000 patients would result in four additional negative appendectomies and four additional cases of perforated appendicitis. This outcome can be weighed against potential prevention of radiation-associated cancer by use of low-dose CT instead of standard-dose CT. We did not measure the carcinogenic risk because the event would be too rare, even with an unrealistically long follow-up. The effective dose for low-dose CT was 2 mSv, which is close to the worldwide average annual exposure to natural radiation sources 25 or to that of three conventional abdominal radiographs. 26 In the standard-dose group, the target effective dose followed institutional normal doses, and the actual dose distribution was similar to survey results for patients with similar body sizes in the USA. 27 According to a previous estimation 7 based on the linear no-threshold theory, 28 use of 2 mSv instead of 8 mSv in roughly 2000 young adults (aged 15–44 years) can prevent one future cancer. If this estimate is projected to 120 000 annual appendiceal CT examinations in a total population of 22 million people aged 15–44 years in South Korea, 4 a 2 mSv dose could prevent 60 cancers each year compared with an 8 mSv dose. This estimation involves unverified assumptions, and whether CT radiation is truly carcinogenic in adults and whether lowering CT radiation dose can truly prevent carcinogenesis is highly debatable. Nevertheless, without evidence strong enough to disprove the carcinogenic risk, it would be prudent for care providers to assume that the risk is not zero and to adhere to the principle of using a dose that is as low as reasonably achievable. Further reduction in radiation dose from 2 mSv would merit further investigation, but only with the following considerations. First, further dose reduction might not have a great advantage in preventing cancers, since 2 mSv is already close to the natural background radiation dose. 25 Second, testing of multiple lower doses would require an unrealistically large sample size and a complex study design if clinical outcomes are measured in a pragmatic setting, as we did in LOCAT. Therefore, a reasonable strategy would be to suggest the lowest achievable dose with a smaller dose-exploration study with diagnostic endpoints ( ClinicalTrials.gov , number NCT02556983 ), and then to validate the suggested dose with a larger trial with clinical endpoints, such as in LOCAT. In the present study, the low-dose and standard-dose groups were similar regarding the overall number of patients with diagnoses other than appendicitis. The low-dose group had more diagnoses of gastroenterocolitis, but fewer diagnoses of gynaecological or urinary diseases, than did the standard-dose group. We did not prespecify alternative diagnosis as an endpoint, since the data would have inevitable limitations, including a small number of patients in each disease category, incompleteness of reference standards, and subjectivity in the adjudication of the results. Generally, young adults who present with suspected appendicitis rarely prove to have a serious chronic or malignant disease. 7 Evidence is accumulating for low-dose CT as an adequate alternative to standard-dose CT for diagnosing urinary stones, 20 colonic diverticulitis, 29 or Crohn's disease. 30 Other alternative diagnoses, such as gastroenterocolitis, pelvic inflammatory disease, complicated adnexal cyst, or urinary tract infection, should primarily be made on the basis of clinical findings or diagnostic tests other than CT. The strengths of LOCAT include its large scale, involving 3074 patients and 161 radiologists (including 105 residents) from 20 hospitals. These figures accounted for 1% of the estimated 320 000 appendiceal CT examinations from the total population aged 15–44 years, 4 10% of the 1049 radiology residents, and a quarter of the 74 teaching hospitals in South Korea during the 32-month study period. With this large scale, the prevalence of appendicitis and negative appendectomy rate in both groups were similar to those in large cohorts 8,31 from the USA, where use of CT is high. Despite the large scale, the representativeness of the LOCAT sample was compromised; therefore, whether the LOCAT results can be generalised to hospitals worldwide remains uncertain. First, all the participating sites were teaching hospitals, mostly large, which could have had better resources or been motivated to use low-dose CT than non-participating hospitals. Second, only a third of the eligible patients were randomly assigned because of logistical reasons in the sites. Third, the catchment area was limited to South Korea, where extremely large body habitus is rare and CT is highly used for diagnosing appendicitis. We recognise the concern that the accuracy of low-dose CT could be compromised in patients with obesity. However, the physical principle that image noise increases with increasing body size does not simply project to modern CT machines, which automatically modulate the X-ray amount to keep consistent image quality across different patient body sizes. Patients with obesity tend to have more intra-abdominal fat, which in fact helps to visualise the appendix on CT images, 32,33 whereas it can be more difficult to identify the appendix in patients with lower BMI, particularly with low-dose CT. LOCAT has other limitations. First, concealment of group allocation was infeasible or not applied to the care providers. The potential optimism or enthusiasm for low-dose CT might have affected the performance of the study procedures, favouring the non-inferiority of the low-dose to the standard-dose procedure. Nonetheless, the results of this pragmatic trial, which incorporate those factors, would be more applicable to usual-care settings. Second, at the time of the study design, we did not anticipate the potential between-group imbalance in the number of appendectomies or confirmed appendicitis cases. Finally, the diagnostic performance of CT could have been inflated because pathological verification of appendicitis was made selectively for patients with positive CT results, and because the pathologists who interpreted the reference standard might have had access to the CT reports. Because of the potential imbalance in the number of appendectomies, those biases might have occurred differently in the low-dose and standard-dose groups. In conclusion, our results show that radiation dose of appendiceal CT for adolescents and young adults can be reduced to 2 mSv without impairing clinical and diagnostic outcomes in teaching hospitals. In view of the vast number of appendiceal CT examinations done worldwide, use of the low-dose technique could prevent a sizeable number of radiation-associated cancers in the future. Correspondence to: Dr Kyoung Ho Lee, Department of Radiology, Seoul National University Bundang Hospital, Seongnam 13620, South Korea firstname.lastname@example.org Contributors Kyoung Ho Lee conceived the study. Kyoung Ho Lee, Yousun Ko, Ji Hoon Park, and Ji Ye Sim reviewed the literature. Kyoung Ho Lee, Kyuseok Kim, Soyeon Ahn, Hye Seung Lee, Sung-Bum Kang, and Kwang Pyo Kim designed the study. Kyoung Ho Lee, Hyuk Jung Kim, Kyuseok Kim, and Mi-Suk Park coordinated the study. Bon Seung Gu coordinated the radiation dose calibration. Min Hee Lee was responsible for radiologist training. Min-Jeong Kim and Sung Bin Park were responsible for CT report standardisation. All the site collaborators gathered the data. Yousun Ko analysed the data and created the tables and figures. Kyoung Ho Lee drafted the manuscript. All the collaborators critically reviewed and approved the manuscript. Seong Whi Cho arranged the authorship policy. Declaration of interests Kyoung Ho Lee received grants from the Korea Health Industry Development Institute, Seoul National University Bundang Hospital, and Dasol Life Science. Min-Jeong Kim received a grant from the Korean Society of Radiology. Cheong-Il Shin received a grant from Seoul National University Bundang Hospital. Hyuk Jung Kim, Min Hee Lee, Min-Jeong Kim, Ji Hoon Park, Sung Bin Park, Seong Sook Hong, Mi Sung Kim, and Jongmee Lee received grants from Dasol Life Science. Each site lead investigator received grants from Bracco Imaging Korea (Hyuk Jung Kim, Min Hee Lee, Min-Jeong Kim, Ji Hoon Park, Seung Joon Choi, Sung Bin Park, Sung Eun Rha, Young Hwan Lee, Seong Sook Hong, Han Jin Cho, Mi Sung Kim, Ji Young Woo, Mi-Suk Park, Jongmee Lee, Seong Whi Cho, Nurhee Hong, Mi Jeong Kim, Cheong-Il Shin, Sang Soo Shin, and Bong Soo Kim). Kwang Pyo Kim received a grant from the Korea Health Industry Development Institute. All other authors declare no competing interests. Acknowledgments We thank all the patients and care providers participating in the trial. LOCAT was endorsed by the Radiology Imaging Network Korea for Clinical Research (RINK-2015-003) of the Korean Society of Radiology. LOCAT was supported by grants mainly from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute of the Ministry of Health & Welfare (HI13C0004 and HI15C1052), Seoul National University Bundang Hospital (04-2011-004, 02-2013-091, 06-2013-066, 14-2014-038, and 13-2015-023), and Dasol Life Science, and partly from Bracco Imaging Korea. The authors are indebted to Roland E Andersson, Young-Suk Lim, Hae Young Kim, Seong Ho Park, Joel G Fletcher, and Tae Kyoung Kim for their advice in improving the manuscript.
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