The RECIST 1.1 trial: Measuring tumor burden to assess response to therapy [Classics Series]

The following study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Radiology: Summaries of Clinically Relevant & Recent Landmark Studies, 1e (The Classics Series).

1. Response to tumor therapy can be assessed by defined target lesions from a subset of measurable lesions. 

2. Disease can be classified as demonstrating complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) based on the radiographic evaluation of target lesions. 

Original Date of Publication: January 2009

Study Rundown: The development of anticancer agents has also necessitated adequate methods to measure tumor response to therapy. In 1979, the World Health Organization (WHO) came together and published a set of criteria to standardize the research definitions of tumor response. Subsequently, researchers continued to disagree on certain definitions, including what constituted a measurable lesion, what the minimum size or number of lesions were to be recorded, how to define disease progression, and how to integrate cross-sectional imaging into response evaluation. These limitations led to modifications of the original WHO criteria, but adoption of these modified criteria remained nonuniform amongst researchers. This heterogeneity in the criteria led to development of new guidelines in 2000, described as the Response evaluation criteria in solid tumors (RECIST), which sought to unify and standardize many of the previously addressed limitations, and provide a consistent framework for the further evaluation of anticancer therapies. The original RECIST guidelines established the conditions for a measurable versus non-measurable lesion, the differences between a target and non-target lesion, and the definitions for therapy response, which included CR, PR, SD and PD.

Since the initial RECIST guidelines, subsequent difficulties and challenges were raised with the defined criteria. Specifically, there was disagreement in the maximum number of lesions to assess in order to measure tumor burden response, how to incorporate pathological lymph nodes into the therapy response, the type of confirmation needed for response in different types of trials, defining disease progression and unequivocal progression, and managing the detection of new lesions. These issues led to development of a RECIST working group to update the original guidelines. A combination of researchers, imaging specialist, and statisticians developed a database of prospective data in order to develop revisions of the original guidelines, named RECIST 1.1. These revised guidelines remained tied to the anatomical evaluation of disease rather than newer assessment tools (i.e., functional or hybrid anatomical/functional assessments of disease).

The RECIST 1.1 guidelines incorporated a large prospective dataset from numerous trials and determined that the maximum number of lesions required to assess tumor burden was 5, reduced from a prior maximum of 10, with a maximum of 2 per organ (down from 5 per organ). Additionally, lymph nodes with a short axis of >15 mm were considered pathological and measurable. These could be defined as target lesions and the short axis measurement were included in the sum of lesions in the overall calculation for tumor response. Another revision of the prior guidelines was that randomized studies with a control arm for comparison did not require confirmation of response, as the control arm allowed for a comparative mechanism to measure response to therapy. Conversely, confirmation of progression is required in non-randomized trials in which the objective response rate is the key endpoint. RECIST 1.1 also updated the definition of disease progression. In addition to the original definition of a 20% increase in sum of the target lesions, it now also required a 5 mm absolute increase in the sum of target lesions (to prevent overcalling progression). Unequivocal progression in a patient with non-target and measurable disease was defined as the substantial worsening of non-target disease, despite stable or responsive disease, that would merit discontinuation of therapy. The use of FDG-PET was also addressed, incorporating it in the assessment of disease progression and/or the identification of new disease. Lastly, while CT and MRI could be used for the assessment of disease, ultrasound was excluded for the use of assessing therapy response.

In-Depth [prospective cohort]: This prospective cohort incorporated data from >6500 patients, including simulation studies and literature reviews. This dataset prospectively documented the change in measurements of solid tumors, which included >18 000 target lesions. Using these data, researchers defined a measurable lesion as one that could be accurately measured, and that the measurement taken was the largest dimension in the plane of measurement, with a minimum size of 10 mm by CT scan (obtained by a CT scanner with a slice thickness no greater than 5 mm). Additionally, a 10 mm caliper measurement by clinical exam can be used (when lesions are superficial, such as a skin nodule), or a 20 mm minimum by chest radiograph to measure index lesions. Lymph nodes were defined as pathological when they measured greater than or equal to 15 mm in the short axis (assessed by CT scan with slice thickness no greater than 5 mm). Lesions that did not meet these criteria were deemed non-measurable. Lesions must have measured >20 mm if non-spiral CT or MRI was used. Lytic bone lesions were confirmed with PET, bone scan, or plain film, but only measured with CT or MRI, and only if they met the prior measurable requirements. Cystic lesions that were thought to represent metastases were measured if they met measurability requirements, but non-cystic lesions were preferred as target lesions. Lesions that have either coalesced into one lesion or broken up into smaller lesions could be measured, but lesions that have broken into smaller ones were treated individually and measured in their respective largest diameters. Lesions that were too small to measure reproducibly but were present on follow up should be assigned a value of 5 mm.

The response to therapy was obtained by assessing the baseline overall tumor burden, and was only be established in patients with at least one measurable lesion. In patients with more than one measurable lesion, a maximum of five measurable target lesions were recorded as representative lesions, with a maximum of two per organ site. RECIST guidelines delineated that these target lesions should be the largest lesions within their respective organs and should have measurements that are reproducible on subsequent measurements. Tumor burden was defined as the sum of the diameters of the target lesions, with the initial measurement taken as the baseline sum diameter. Once target lesions were identified, they should be used in subsequent evaluation studies. All other lesions identified are labeled as non-target lesions.

CR was defined as the disappearance of all target lesions, with the reduction of all pathological lymph nodes to <10 mm. PR was defined as at least a 30% decrease in the sum of the target lesions, in comparison to the baseline sum diameter. PD was defined as a 20% increase in the sum of the diameters in comparison to the smallest sum of diameters with an absolute increase of at least 5 mm. In addition, any new lesion was considered progressive disease. SD was defined as meeting neither the criteria for partial response nor for progressive disease, in comparison to the smallest sum of diameters.

These guidelines allow for the assessment of therapy response in patients undergoing antitumor therapy, but they rely on the assumption that all disease response is manifested as a steady decline in tumor burden. Subsequent research in novel treatment modalities, such as immune therapy, has suggested that positive disease response may not follow a linear decline in tumor burden, but in fact may have a small period of tumor burden increase or even new lesions on a short-term basis. However, with continued therapy, the overall disease burden may improve or continue to be stable over a long period of time, and suggests that the RECIST criteria may not encompass all types of therapy response, in particular with new targeted therapies.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer. 2009 Jan 1;45(2):228–47.

Response Category Definition
CR –        Resolution of all known disease

–        Malignant nodes <10 mm

PR –        Measurable target lesions

–        30% decrease in the sum of longest diameter

–        No evidence of progression of other disease

SD –        Nonsufficient shrinkage to qualify of PR OR Nonsufficient increase to qualify for PD

–        Reference: smallest sum of diameters

PD –        Measurable target lesions

–        20% increase in sum of longest diameter

–        Minimum absolute increase of 5 mm

–        Reference: smallest sum in study or appearance of new lesions

Table I. Recist 1.1 criteria.  CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.

  • Measurable lesion: longest diameter measurement of tumor lesions ≥10 mm (CT or skin caliper); ≥20 mm if by chest radiograph.  
  • Measurable node: ≥15 mm in short axis.
  • Baseline sum: sum of diameters of target lesions, nodes, and longest diameters of other lesions.
  • Disease burden assessed at baseline: measurable target lesions, up to 5 total (2 per organ); other lesions nontarget.

Click to read the study in the European Journal of Cancer

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