ORIGINAL ARTICLE Korean J Intern Med 2019;34:608-617 https://doi.org/10.3904/kjim.2017.063 Comparison of the morphologic criteria (RECIST) and metabolic criteria (EORTC and PERCIST) in tumor response assessments: a pooled analysis Hong Deok Kim, Bum Jun Kim, Hyeong Su Kim, and Jung Han Kim Division of Hemato-Oncology, Background/Aims: The Positron Emission Tomography Response Criteria in Sol- Department of Internal Medicine, id Tumors (PERCIST) or European Organization for Research and Treatment of Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea Cancer (EORTC) criteria are used to assess metabolic tumor responses. However, tumor responses have shown considerable discrepancies between the morpholog- ic criteria (Response Evaluation Criteria in Solid Tumors [RECIST]) and metabol- ic criteria. We performed this pooled study to compare the RECIST and metabol- ic criteria in the assessment of tumor responses. Methods: Electronic databases were searched for eligible articles with the terms “RECIST,” “PERCIST,” or “EORTC criteria.” The level of concordance in the tu- mor responses between the two criteria was estimated using κ statistics. Results: A total of 216 patients were collected from eight studies comparing the RECIST and EORTC criteria. The agreement of tumor responses between the two criteria was moderate (κ = 0.447). Eighty-six patients (39.8%) showed disagree- ment: tumor response was upgraded in 70 patients and downgraded in 16 when adopting the EORTC criteria. The EORTC criteria significantly increased the overall response rate (53% vs. 28%, p < 0.0001). The agreement of tumor responses between the RECIST and PERCIST was deemed fair (κ = 0.389). Of 407 patients Received : February 9, 2017 from nine studies, 181 (44.5%) showed a discrepancy: using the PERCIST, tumor Revised : July 10, 2017 response were upgraded in 151 patients and downgraded in 30. When adopting Accepted : July 19, 2017 the PERCIST, the overall response rate was also significantly increased from 30% Correspondence to to 55% (p < 0.0001). Jung Han Kim, M.D. Conclusions: This pooled analysis demonstrates that the concordance of tumor Division of Hemato-Oncol- responses between the morphologic criteria and metabolic criteria is not excel- ogy, Department of Internal Medicine, Hallym University lent. When adopting the metabolic criteria instead of the RECIST, overall re- Kangnam Sacred Heart Hospital, sponse rates were significantly increased. 1 Singil-ro, Yeongdeungpo-gu, Seoul 07441, Korea Keywords: Response evaluation criteria in solid tumors; Positron emission to- Tel: +82-2-829-5414 Fax: +82-2-846-4669 mography response criteria in solid tumors; European Organization for Research E-mail: [email protected] and Treatment of Cancer criteria; Tumor response INTRODUCTION Response Evaluation Criteria in Solid Tumors (RECIST) [2,3] are the morphologic criteria commonly used to as- The World Health Organization guidelines [1] and the sess tumor response in clinical practice. However, these Copyright © 2019 The Korean Association of Internal Medicine pISSN 1226-3303 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ eISSN 2005-6648 by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. http://www.kjim.org Kim HD, et al. Comparison of RECIST and metabolic criteria criteria depending on the size changes based on com- METHODS puted tomography (CT) have limitations in tumors with obscure margins, cystic lesion, or scar tissue. In particu- Search strategy lar, measuring the longest diameter of lesions on CT is A computerized systematic search of the electronic da- not always possible in gastrointestinal tumors. Because tabases PubMed, Embase, Scopus, and Google Scholar patients treated with targeted agents were not included (up to June 2017) was carried out to find articles with the in the data warehouse [4] when the RECIST version 1.1 following terms in their titles, abstracts, or keywords: was revised [3], there has also been concern regarding “RECIST,” “PERCIST,” or “‘EORTC criteria.” In addi- the assessment of tumor responses with the RECIST in tion, we checked all the references of identified relevant patients receiving targeted agents [5]. Molecular target- articles and reviews. We also used the “related articles” ed agents tend to induce necrotic or cystic change, not feature in PubMed to identify relevant articles. tumor shrinkage, in solid tumors [6]. Therefore, mor- phologic response criteria may be not well suited for Study selection criteria assessing the efficacy of targeted therapies that stabilize Studies comparing tumor responses by using the RE- diseases. CIST and metabolic criteria (EORTC or PERCIST) were [18F]-fluorodeoxyglucose ([18F]-FDG) uptake is en- considered for inclusion in this pooled study. As the RE- hanced in most malignant tumors which in turn can CIST 1.1 showed a high concordance with the RECIST be measured by positron emission tomography (PET). 1.0 in the assessment of tumor responses [28,29], we in- [18F]-FDG PET has been adopted as a new method for cluded both versions without distinction in the analy- the diagnosis and staging of solid tumors. PET is also sis. For a more accurate comparison, however, articles increasingly being used to monitor tumor responses to adopting the modified RECIST versions developed for anti-cancer therapies. It can allow the assessment of tu- specific types of tumors were excluded. The searched ar- mor response even in the absence of anatomical chang- ticles were screened again by reviewing the full text, and es [7-9]. There are two sets of criteria using FDG PET the original articles that compared tumor responses be- to quantify metabolic changes to anti-cancer treatment: tween the morphologic criteria (RECIST 1.0 or RECIST the criteria developed by the European Organization for 1.1) and metabolic criteria (PERCIST or EORTC) were Research and Treatment of Cancer (EORTC) criteria [10] included in the final analysis. and the Positron Emission Tomography Response Cri- teria in Solid Tumors (PERCIST) [11]. Tumor response Tumor response assessment evaluations with the PERCIST and EORTC criteria have The tumor responses according to the RECIST in each shown almost perfect agreement and correlated well study were defined as follows [2,3]: (1) complete response with survival [12,13]. The metabolic response criteria (CR): disappearance of all lesions; (2) partial response may provide clinicians with a more accurate assessment (PR): at least a 30% decrease in the sum of diameters of of therapeutic response at an earlier stage of treatment the target lesions and no new lesions; (3) progressive dis- course. However, their usefulness and advantage over ease (PD): more than a 20% increase in the sum of diam- the morphologic criteria (RECIST) need to be further eters of the target lesions (and also an absolute increase investigated. of at least 5 mm in the RECIST 1.1) or the appearance of The assessment of tumor responses between the mor- new lesions on CT (or PET in the RECIST 1.1); and (4) phologic criteria and metabolic criteria has shown con- stable disease (SD): neither sufficient shrinkage to quali- siderable discrepancies in a series of studies with a small fy as PR nor sufficient increase to qualify as PD. number of patients [14-27]. We performed this pooled The tumor response guidelines for the PERCIST and study to compare tumor response assessment between EORTC criteria are briefly summarized in Table 1. the morphologic criteria (RECIST 1.0 and RECIST 1.1) and metabolic criteria (EORTC criteria and PERCIST) in Statistics patients with solid tumors. The overall response rate (ORR) was defined as the per- centage of patients with CR or PR (as determined by the https://doi.org/10.3904/kjim.2017.063 www.kjim.org 609 The Korean Journal of Internal Medicine Vol. 34, No. 3, May 2019 Table 1. Tumor response assessment by two metabolic criteria (EORTC criteria and PERCIST) EORTC PERCIST Complete metabolic response (CMR) Complete resolution of FDG uptake Complete resolution of FDG uptake in in all lesions all lesions Partial metabolic response (PMR) ≥ 25% Reduction in the sum of ≥ 30% Reduction of the SULpeak and an SUVmax after more than one cycle absolute drop of 0.8 SULpeak units of treatment Progressive metabolic disease (PMD) ≥ 25% Increase in the sum of ≥ 30% Increase in the SULpeak of the SUVmax or appearance of new FDG uptake and an absolute increase of FDG-avid lesions 0.8 SULpeak, or appearance of FDG-avid new lesions Stable metabolic disease (SMD) Not qualify for CMR, PMR, or PMD Not qualify for CMR, PMR, or PMD EORTC, European Organization Research and Treatment of Cancer; PERCIST, Positron Emission Tomography Response Criteria in Solid Tumors; FDG, fluorodeoxyglucose; SUVmax, maximum standardized uptake value; SULpeak, peak lean body mass SUV. two RECIST versions) and those with complete metabol- 132 Potentially relevant studies identified from ic response (CMR) or partial metabolic response (PMR) electronic databases search (as determined by the PERCIST or EORTC criteria). The ORRs between the two groups were compared by us- 110 Studies excluded after screening titles and abstracts ing the McNemar test and p values less than 0.05 were considered significant. The level of agreement in tumor 22 Studies retrieved for more responses between the two criteria was estimated using detailed assessment unweighted κ statistics. The agreement was interpreted as poor (κ < 0), slight (κ = 0 to 0.20), fair (κ = 0.21 to 0.40), 5 Studies with no details of moderate (κ = 0.41 to 0.60), substantial (κ = 0.61 to 0.80), response classification and almost perfect (κ > 0.80) [30]. 3 Studies using modified RECIST Ethics This study did not require approval by an ethics com- 14 Studies included in the pooled analysis 5 Comparing RECIST and EORTC mittee because it was a pooled analysis with systematic 6 Comparing RECIST and PERCIST review of previously published studies.