Imaging is integral to the care of oncologic patients, including diagnosis, staging, and treatment response assessment, and is instrumental in guiding patient management in the majority of cases. Imaging is also fundamental to clinical trials, for both patient inclusion and response assessment. Since the introduction of the first tumor response assessment criteria by the World Health Organization in 1981, several modifications have further refined standard imaging criteria to assess response to cancer therapies . Later modifications incorporated CT and MRI and helped to maintain consistency, uniformity, and reproducibility of standardized response assessment criteria in clinical trials. Response Evaluation Criteria in Solid Tumor (RECIST version 1.0) introduced in 2000 by the International Working Group, and revised in 2009 (RECIST version 1.1), further clarified, simplified, and refined the assessment criteria providing a “common language” in tumor response assessment based on imaging . RECIST provides an objective assessment of tumor response to cytotoxic chemotherapy, based on the morphologic manifestation of change in tumor (lesion) size. RECIST provides a detailed reproducible method of defining total tumor burden including lesion selection (target and nontarget lesions), and measurement technique to maintain consistency at pre and post-treatment imaging evaluation and across different trials. In contrast to bidimensional measurement of a tumor lesion by WHO criteria, RECIST uses unidimensional largest diameter lesion measurement with sum of longest dimensions of target lesions defining the total disease burden. Based on the interval change in tumor burden from baseline (primarily based on lesion size), these criteria assign the treatment response into one of four categories—complete response, partial response, stable disease, and progressive disease. While RECIST remains the most widely used response assessment criteria, it is limited for assessment of noncytotoxic therapies such as immunotherapies and loco-regional therapies, which often demonstrate relative size stability and even transient increase in size (with immunotherapy) in successfully treated lesions. Increasingly, size has been revealed as an imperfect marker of viability in such targeted therapies.
Targeted loco-regional therapies (radiofrequency ablation, transarterial chemoembolization [TACE], stereotactic body radiotherapy (SBRT) and localized forms of intra-arterial radioembolization) for certain localized tumors cause biological response by inducing direct tumor necrosis, with or without morphologic changes in lesion size. True treatment response assessment in such cases may be suboptimal if conventional RECIST criteria are used, as it does not take into consideration biologic response of tumor necrosis. A primary example is response to loco-regional therapy in hepatocellular carcinoma (HCC). Non-invasive diagnosis of HCC on multiphasic CT and MR generally depends on arterial phase enhancement and washout as defined by the American College of Radiology’s Liver Imaging Reporting and Data System , American Association for the Study of Liver Diseases, and the Organ Procurement and Transplantation Network . Targeted loco-regional therapy is recommended for localized HCC in patients who are not suitable candidates for surgical resection or transplantation . Persistent arterial phase hyperenhancement is the best known surrogate for viability in HCC, so treatment response in loco-regional therapy is best assessed by evaluating degree of residual arterial enhancement and thus residual disease. In 2000, the European Association for the Study of the Liver added tumor necrosis as a biological marker to the WHO criteria and used bidimensional measurement of arterial enhancing component of the HCC to define viable disease . In 2010, modified RECIST (mRECIST) was introduced with similar logic, incorporating the concept of arterial phase hyperenhancement into the widely used and validated unidimensional RECIST criteria . mRECIST currently remains the gold standard for assessing radiological treatment response in HCC . Both mRECIST and European Association for the Study of the Liver have shown good concordance and strong prognostic value in overall survival of HCC patients treated with loco-regional therapies .
What are the radiological implications of these tumor response criteria in routine practice? As highlighted in the paper by Choi et al. in this issue of Academic Radiology , there are several. The authors evaluated intra and interobserver reproducibility of response categorization using mRECIST in patients with HCC treated with TACE, using MDCT. A major strength of their study is independent review of tumor response in 97 patients with HCC treated with TACE by four radiologists with varying experiences, reflecting a real-life clinical practice. They show higher agreement in target lesion evaluation in cases with agreement in overall tumor response, highlighting the relevance of identifying, and selecting target lesion(s). While the RECIST and mRECIST response criteria were introduced primarily for consistency in clinical trials, they have importance for use in routine image interpretation to standardize lesion selection, measurement, and treatment changes between readers and studies that can impact clinical decision making. For example, radiology reports identifying and describing residual enhancing tumor in post TACE treated HCC, or raising possibility of transient pseudoprogression in patients on immunotherapy, influences clinical management. Another interesting finding is the higher intraobserver reproducibility of treatment response and high intraclass correlation coefficient of lesion measurement among experienced readers, which may partly be attributed to increased involvement and participation of experienced readers in multidisciplinary tumor boards and or collaborative oncology research promoting more exposure and understanding to various tumor response criteria.
Most importantly, the study shows lower confidence in target lesion selection and response assessment among less experienced radiologists, as well as improved interobserver reproducibility on second review, emphasizing the need for dedicated education in tumor response criteria. Understandably, there is lack of dedicated teaching and training targeted to response criteria among trainees since these criteria are rarely used in our routine image interpretation. Some exception may exist for radiologists who are part of funded clinical trials or collaborative oncology research that provides dedicated time for tumor measurement and thus increased familiarity to these criteria. To this end, periodic review of dedicated teaching material, articles and resources of various relevant response criteria by oncologic radiologists at departmental conferences, multidisciplinary boards and/or journal clubs may serve to improve understanding and confidence in tumor lesion identification, measurement, and treatment assessment.
The authors conclude that given moderate to excellent intra and interobserver reproducibility of readers for overall response using mRECIST in their study, this criterion can be applied to daily practice. Also, there remains an opportunity to explore and collaborate with oncologists, adding value to the ongoing trials and research with our radiological expertise, as imaging is at the crux of response assessment criteria.
References
1. Miller AB, Hoogstraten B, Staquet M, et. al.: Reporting results of cancer treatment. Cancer 1981; 47: pp. 207-214.
2. Therasse P, Arbuck SG, Eisenhauer EA, et. al.: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: pp. 205-216.
3. Eisenhauer EA, Therasse P, Bogaerts J, et. al.: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: pp. 228-247.
4. Mitchell DG, Bruix J, Sherman M, et. al.: LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. Hepatology 2015; 61: pp. 1056-1065.
5. Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology 2011; 53: pp. 1020-1022.
6. Heimbach JK, Kulik LM, Finn RS, et. al.: AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018; 67: pp. 358-380.
7. Bruix J1, Sherman M, Llovet JM, et. al.: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35: pp. 421-430.
8. Lencioni R1, Llovet JM: Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30: pp. 52-60.
9. Kim MiNa, Kim BeomKyung, Han Kwang-Hyub, et. al.: Evolution from WHO to EASL and mRECIST for hepatocellular carcinoma: considerations for tumor response assessment. Expert Rev Gastroenterol Hepatol 2015; 9: pp. 335-348.
10. Vincenzi B, Di Maio M, Silletta M, et. al.: Prognostic relevance of objective response according to EASL criteria and mRECIST criteria in hepatocellular carcinoma patients treated with loco-regional therapies: a literature-based meta-analysis. PLoS One 2015; 10:
11. Choi MH, Choi J, Park GE, et. al.: Reproducibility of mRECIST in measurement and response assessment for hepatocellular carcinoma treated by transarterial chemoembolization. Acad Radiol 2018; (In press)