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© 2023 Clinical Data Interchange Standards Consortium, Inc. All rights reserved. 

1 Introduction

This document describes the CDISC implementation of the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) disease response criteria.

CDISC is not including an annotated case report form (CRF) for this disease response supplement as the primary purpose of the supplement is to show examples of how to implement the disease response criteria in CDISC data standards domains.

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Although the United States Food and Drug Administration (US FDA) has provided input with regard to this supplement, this input does not constitute US FDA endorsement of any particular instrument. 

2 Copyright Status

The RECIST Working Group and European Journal of Cancer (EJC) own the copyright for the RECIST 1.1 guidelines and have made the RECIST 1.1 guidelines available for non-commercial purposes exempt from copyright restrictions. All other rights are reserved.CDISC has included this supplement in the CDISC inventory of QRS data standards supplements. Hence, CDISC developed data standards for tumor identification, tumor results, and disease response, and applied these to RECIST 1.1.

The CDISC documentation of the criteria consists of: (1) controlled terminology and (2) standard data structures with examples.

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CDISC has developed this documentation at no cost to the copyright holder or any additional cost to users of the criteria beyond the normal license fees charged by the copyright holder.

References for the RECIST 1.1:

• E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumours; Revised RECIST guideline (version 1.1). European Journal of Cancer 2009; 45:228-247.
  
• https://recist.eortc.org/recist-1-1-2/

3 The Oncology Disease Response and Supporting Domains Supporting Domains Model for RECIST 1.1

RECIST 1.1 is a set of criteria used  to to evaluate the activity and efficacy of anti-neoplastic antineoplastic agents in solid tumors. The " The Oncology Disease Response and Supporting Domains Model for RECIST 1.1 " encompasses the subset of SDTMIG domains used for the representation of RECIST 1.1 disease response and supporting tumor/lesion data in oncology studies. The These SDTMIG domains used include:

• Disease Response and Clin Classification (RS) is a findings domain used to represent disease response findings and QRS clinical classifications instruments. The disease responses based on RECIST 1.1 are represented in RS. 
• Tumor/Lesion Identification Identification (TU) is a findings domain. The supporting tumor identification of RECIST 1.1 target, non-target, and new tumors are represented in the TU domain. 
• Tumor/Lesion Results (TR) is a findings domain. The supporting tumor measurements and assessments of the RECIST 1.1 target, non-target and new tumors are represented in the TR domain.

Note that the Procedures (PR) domain is not required for RECIST 1.1 but it may be used to represent scan data including medical photography data.

These domains are related using RSLNKGRP, TULNKID, TUREFID, TRLNKID, TRLNKGRP, TRREFID, and PRREFID. See Section 5, RELREC, for more information on the relationships and an example RELREC dataset.

CDISC Biomedical Concepts biomedical concepts are available for RECIST 1.1 following the twothe 2-layered approach:

• Conceptual/abstract layer that provides standards-agnostic, unambiguous semantic definition largely based on NCIt concepts. concepts
• Implementation layer based on valid CDISC dataset specializations that provide value-level metadata definitions that facilitate metadata-driven automation.

SDTM dataset specializations have been defined for TU, TR, and RS datasets. They are retrievable via the CDISC Library API as JSON output. See the CDISC Biomedical Concepts page for more information https://www.cdisc.org/cdisc-biomedical-concepts.

3.1 Assumptions for the Oncology Disease Response and Supporting Domains Model

All assumptions and business rules described in the SDTMIG are are applicable to this supplement. Additional assumptions specific to the RECIST to RECIST 1.1 are 1 are listed below.

1. The CDISC Oncology Codetable on the CDISC website (available at https://www.cdisc.org/standards/terminology/controlled-terminology) contains the valid value list for the tests in the TU, TR, and RS domains. 

   1. RSORRES is populated with the original result and RSSTRESC is populated with the standardized character result according to the associated controlled terminology. For example, RSORRES = "CR" and RSSTRESC = "CR" where "CR" is a valid value in the associated controlled terminology.

   2. TUORRES is populated with the original result and TUSTRESC is populated with the standardized character result according to the associated controlled terminology.  For For example, TUORRES = "TARGET" and TUSTRESC = "TARGET" where "TARGET" is a valid value in the associated controlled terminology.

   3. For the TR domain, TRORRES and TRSTRESC can contain numeric or character results and TRSTRESN is only populated for numeric results. There are situations when a character result in TRORRES is standardized to a numeric representation of the result in TRSTRESC and TRSTRESN.  

3.2 General Points on Representation of Data within the Oncology Disease Response Domains Response Domains for RECIST 1.1

In RECIST 1.1, a subject's tumors are identified as target tumors, non-target tumors, and new tumors. At a specific disease assessment timepoint, the overall response in RECIST 1.1 is based on measurements of target tumors (target response), qualitative assessments of non-target tumors (non-target response) and the appearance of new tumors. Subjects with at least one 1 target tumor can have overall response of CR (Complete Response), PR (Partial Response), SD (Stable Disease), PD (Progressive Disease) and NE (Not Evaluable). Subjects with only non-measurable nonmeasurable disease (i.e., no target tumors) can have overall response of CR (Complete Response), NON-CR/NON-PD, PD (Progressive Disease), and NE (Not Evaluable).

Target tumors are measured in the longest diameter except when the location is a lymph node, then when they are measured in the longest perpendicular. The examples in this disease response supplement use TRTESTCD = "LDIAM" (Longest Diameter) for measurements of non-lymph node target tumors and TRTESTCD = "LPERP" (Longest Perpendicular) for measurements of lymph node target tumors. The SDTMIG examples have previously used TRTESTCD = "DIAMETER" (Diameter) for measurements of both lymph nodes and non-lymph nodes. Either representation is acceptable for RECIST 1.1. The latter approach requires looking at the anatomical location in conjunction with the TRTESTCD to TRTESTCD to know whether the diameter was measured in the longest diameter or the longest perpendicular. The " LDIAM " and " LPERP " tests provide more specificity in the TRTESTCD itself and does do not required require looking to the anatomical location. In addition, "the LDIAM " and " LPERP " tests are tests used in other disease response criteria so ; the use of these two 2 tests provides standardization that work across criteria for the same measurement. Some sponsors prefer the approach used within this disease response supplement due to these reasons. 

Target tumors may split (fragment) and/or merge (coalesce) during a study. See example Section 4.2, Example 2 for a detailed example on : Split and Merged Tumors, for the preferred representation of the measurements of split and merged tumors. Regardless of the representation of split and merged lesions, it is essential that the summation of the diameters is accurate.

In RECIST1.1, the following calculations are used in determination of the target response: sum of the diameters of target tumors (target sum), percentage change from baseline in the target sum, and percentage change from nadir in the target sum (smallest target sum at any assessment). These are referred to as summary values in the examples below. These summary values are not typically collected/calculated in investigator CRFs, but they rather are usually provided by independent assessors.   When not derived in EDC, summary values not in the collected data may be derived in the analysis datasets (i.e., ADaM).

RECIST 1.1 recommends using a standardized value of 5 mm is used in the calculation of sum of diameters when a target tumor is too small to measure. Note that this imputation should only be done when the lesion diameter is too small to measure.   When a numerical value is given for the lesion diameter, then that value will be used even if the diameter is less than 5 mm. The original or collected value "TOO SMALL TO MEASURE" should be represented in the TRORRES variable and the standardized value should be represented in the TRSTRESC and TRSTRESN variables. For absent non-lymph node target tumors, 0 mm is used in the calculation of the target sum. The longest perpendicular measurements of lymph node target tumors which are pathological (>= 10 mm) or non-pathological (< 10 mm) are included in the target sum. 

The examples in this disease response supplement use RSTESTCD = "NEWLPROG" (New Lesion Progression)  to to indicate whether a new lesion is equivocal or unequivocal. There are different methods of collecting data when there is an equivocal new lesion. Some sponsors update the Overall Response overall response when unequivocal evidence of a new lesion has been later confirmed (i.e., documented as unequivocal). Other sponsors programmatically derive programmatically derive the new lesion progression date as the date when the new the new lesion was first identified during the analysis. RSTESTCD = "NEWLSIND" can have RSORRES = "Y" or RSORRES = "N" values only. This test can be used if the sponsor collects yes and no responses to indicate new lesion(s) were identified at the disease assessment timepoint.

"NE" (Not Evaluable) is a standard result in the Oncology Response Assessment Result codelist (ONCRSR) which is applicable to RECIST 1.1. Therefore, in RS, "NE" (Not Evaluable) is a valid RSORRES/RSSTRESC for RSTEST = "Overall Response". For RS, a suppqual supplemental qualifier for "Reason Response Not Evaluable" (RSREASNE) has been used in some examples. However, in TR, the current modeling for NE (not evaluable) results follows the approach where TRSTAT is populated with "NOT DONE".  TRSTAT = "NOT DONE" means that the result was missing and the reason that the result was missing is mapped to TRREASND. The TRREASND values cover reasons such as scan was not performed or the various reason that the tumor was not evaluable. This modelling modeling does not always explicitly or consistently identify the tumors which are not evaluable but some of the examples include "NOT EVALUABLE" in the TRREASND.

In the case where there is an independent review and the investigator identified tumors at baseline but the independent assessor found no evidence of disease (NED) at baseline, this can be represented by a an RS record with RSTEST = "Overall Response" and , RSORRES = "NED", and RSSTRESC = "NED".

The Per the SDTMIG states , "When a clinical classification result is based on multiple procedures/scans/images/physical exams performed on different dates, RSDTC may be derived." Some sponsors assign or derive the date of overall response (RSDTC) associated with the disease assessment timepoint, and some sponsors collect the date of overall response (RSDTC) associated with the disease assessment timepoint and provide instructions to the site/vendor on their convention on how to populate it when there is more than one 1 evaluation date. In the RS examples, when there are multiple dates of evaluation performed as part of the disease assessment timepoint, the RSDTC is populated using the following commonly used convention (either entered by the investigator, assigned by the sponsor, or assigned by an independent assessor):  For For responses of CR (Complete Response) and PR (Partial Response), the latest date associated with the evaluation is used; for responses of PD (Progressive Disease), the earliest date associated with an evaluation is used. This convention is based on the following concepts:  when When evaluating measures of disease burden over time such as (e.g., duration of response or , progression-free survival), it is generally considered conservative to assign a negative outcome (e.g., such as disease progression, ) to the date the assessment is initiated but not to assign a date to a positive response until the assessment is completed. For SD (Stable Disease), different conventions have been used in industry and the rationale varies. For the examples belowin this supplement, the convention used for SD was is to assign the earliest date to RSDTC. However, picking the latest date is acceptable and a common approach. For NE (Not evaluableEvaluable), a date associated with the assessment is required but it generally does not impact the analysis, so either the earliest or latest date can be used.

In TR, the TRDTC is populated with the date of tumor/lesion assessment/measurement , (i.e., the date of the scan, image, or physical exam). In the examples, the summary results (e.g., Sum of Diameter) do not have TRMETHOD and TRDTC associated with them.   However, if an appropriate TRDTC is available, it can be populated. In TR, scans which are not performed do not have a TRDTC populated.

Note that examples :

1. Examples in this

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1. supplement are based on

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1. assumptions about the data collection forms. For example, the collection of split and merged tumors may be collected in different ways depending on the form design and system limitations. The preferred SDTM data representation is shown in the examples.

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1. Examples in this

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1. supplement assume that no protocol modifications were made to RECIST 1.1.

4 Examples for the Oncology Disease Response Domains Model for Response Domains Model for RECIST 1.1

4.1 Example 1: Investigator Assessment of Subject with Lymph Nodes as Target Lesions

This RECIST 1.1 example to show shows investigator response (RS) data and the underlying tumor identification (TU), tumor results (TR), and procedure (PR) data. The example shows the case where In this example, lymph nodes are selected as target lesions. The tumor The tumor identifier is in TULNKID and matches TRLNKIDs in the TR DomainTRLNKIDs in the TR domain. The image identifiers are in TUREFID and TRREFID in the TU and TR domains, respectively, and they match the image identifiers in PRREFID in the PR Domain.

4.1.1 RS Domain Model

The rsfollowing rs.xpt table below shows the shows the terminology used to implement RECIST implement RECIST 1.1 in the RS domain1 in the RS domain. This example shows the data for one 1 subject collected at the week 6, week 12, and subsequent 8-week follow-up visits. Note: Sponsor Sponsors may include the New Lesion Indicator test (RSTESTCD = "NEWLIND") at every timepoint if the new lesion yes or no question is part of the data collection.

The following supprs.xpt table below shows the data on the reason that the response was not evaluable (QNAM = "RSREASNE") in the in the case where the reason is collected.

4.1.2 TU Domain Model

The  tufollowing tu.xpt table below shows table shows the terminology used to implement RECIST implement RECIST 1.1 in the TU domain1 in the TU domain. This example shows the data for one 1 subject at screening and at weeks 36 and 44, where new lesions are identified. In this example, lymph nodes are selected as target tumors. In RECIST 1.1, target lymph node tumors are measured in the longest perpendicular (TRTESTCD = "LPERP") in the TR domain. The image identifier is in TUREFID and matches a PRREFID in the PR Domaindomain.

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