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© 2019 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.

The representation of data collected for the disease response criteria is based on the Study Data Tabulation Model Implementation Guide (SDTMIG), which can be found at the CDISC website at: (https://www.cdisc.org/standards/foundational/sdtmig).

These specific implementation details for the disease response criteria are meant to be used in conjunction with the SDTMIG. All CDISC Disease Response documentation packages can be found on the CDISC web site at: (https://www.cdisc.org/foundational/qrs).

The CDISC Intellectual Property Policy can be found on the CDISC web site at: (https://www.cdisc.org/about/bylaws).

1.1 Representations and Warranties, Limitations of Liability, and Disclaimers

This document is a supplement to the SDTMIG for Human Clinical Trials and is covered under Appendix F of that document, which describes representations, warranties, limitations of liability, and disclaimers. Please see Appendix F of the SDTMIG for a complete version of this material.

CDISC specifies how to structure the data that has been collected in a database, not what should be collected or how to conduct clinical assessments or protocols.

2 Copyright Status

The RECIST Working Group owns the copyright for the RECIST 1.1 disease response criteria. CDISC has developed data standards for tumor identification, tumor results and disease response, and applied these to RECIST 1.1. Examples were developed to represent RECIST 1.1 and were included in the CDISC library of QRS data standards supplements. There may be many versions of the disease response criteria in the public domain or copyrighted. CDISC has chosen to use this version as the data standard.

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

Note: CDISC controlled terminology is maintained by National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS). The most recent version should be accessed through the CDISC website (https://www.cdisc.org/standards/semantics/terminology).

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.

CDISC acknowledges the RECIST Working Group and the European Journal of Cancer (EJC) for having the RECIST 1.1 available for free.

References for the Response Evaluation Criteria in Solid Tumors Version 1.1 (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.
• http://recist.eortc.org/recist-1-1-2/, accessed 2019-06-21.
  

3 The Oncology Disease Response Domains Model for RECIST 1.1

3.1 Assumptions for the Oncology Disease Response Domains

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

RECIST 1.1 is a set of criteria used to evaluate the activity and efficacy of new cancer therapeutics in solid tumors.

1. The Oncology Codetable on the CDISC website at https://www.cdisc.org/standards/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. 

   2. TUORRES is populated with the original result and TUSTRESC is populated with the standardized character result according to 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

The examples in this disease response supplement are based on assumptions about the data collection forms.  It is understood that existing data collection form cannot be updated mid study. However, the preferred SDTM data is shown in the examples.

The examples in this disease response supplement use the TRTESTCDs of "LDIAM" (Longest Diameter) for measurements of non-lymph node target tumors and "LPERP" (Longest Perpendicular) for measurements in the short axis of lymph node target tumors. The SDTMIG uses the TRTESTCD "DIAMETER" (Diameter) for measurements of target tumors, i.e., the TRTESTCD of "DIAMETER" can be used for measurements of both lymph nodes and non-lymph nodes. Either representation is acceptable for RECIST 1.1 in SDTM. The latter approach requires looking at the anatomical location in conjunction with the TRTESTCD in order to know whether the diameter was measured in the longest diameter or the short axis. The "LDIAM" and "LPERP" tests provide more specificity in the TRTESTCD itself and does not required looking to the anatomical location. In addition, "LDIAM" and "LPERP" are tests used in other disease response criteria so the use of these two tests provides standardization that work across criteria for the same measurement. Some sponsors much prefer the approach used within this disease response supplement due to these reasons.

The examples in this disease response supplement use the RSTESTCD "NEWLPROG" (New Lesion Progression) in order to indicate whether a new lesion is equivocal or unequivocal. There are different methods of collecting data when there is a equivocal new lesion. Some sponsors update the Overall Response when unequivocal evidence of a new lesion has been later been confirmed (i.e., documented as unequivocal). Other sponsors during the analysis, programmatically derive the new lesion progression date as the date when the new lesion was first identified. The RSTESTCD "NEWLSIND" can have "Y" or "N" RSORRES 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.

In the case where no evidence of disease was found at baseline, this can be represented by a RS record with RSTEST = "Overall Response" and RSORRES="NED" and RSSTRESC="NED".

"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 for Reason Not Evaluable (REASNE) has been used in the 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 results 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 does not always explicitly or consistently identify the tumors which are not evaluable but some of the examples include "NOT EVALUABLE" in the TRREASND.

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 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 responses of CR (Complete Response) and PR (Partial Response), the latest date associated with the evaluation is used; for responses of PD (Progressive Disease) and SD (Stable Disease), the earliest date associated with an evaluation is used. This convention is based on the following concepts: when evaluating measures of disease burden over time such as duration of response or progression free survival, it is generally considered conservative to assign a negative outcome 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. A SD (Stable Disease) implies no change in disease status for at least a minimum time. While the absence of progression can only be certain with a complete evaluation, the status of the first evaluations cannot be carried forward to the last evaluation date in the assessment; therefore using the earliest date gives the most conservative approach when determining if a subject met the criteria for stable disease. For NE (Not evaluable), 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. The summary results (e.g., Sum of Diameter) do not have TRMETHOD and TRDTC associated with them.  Also, scans which are not performed do not have a TRDTC populated. 

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

4.1 Example 1: RECIST 1.1 example to show investigator response (RS) data and the underlying tumor identification (TU), tumor results (TR), procedure (PR) data and trial disease assessment (TD) data.  

The example shows the case where lymph nodes are selected as target lesions. The tumor identifier is in TULNKID and matches TRLNKIDs 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 rs.xpt table below shows the terminology used to implement RECIST 1.1 in the RS domain. This example shows the data for one subject collected at the week 6, week 12 and subsequent 8-week follow-up visits.

4.1.2 TU Domain Model

The tu.xpt table below shows the terminology used to implement RECIST 1.1 in the TU domain. This example shows the data for one 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 short axis (TRTESTCD = "LPERP" and TRTEST = "Longest Perpendicular") in the TR domain. The image identifier is in TUREFID and matches a PRREFID in the PR Domain.

4.1.3 TR Domain Model

The tr.xpt table below shows the terminology used to implement RECIST 1.1 in the TR domain. This example shows the data for one subject collected at screening, week 6, week 12 and subsequent 8-week follow-up visits. It shows measurements of lymph nodes, i.e., longest perpendicular (measured in the short axis), as well as measurements of other non-lymph node Target tumors, i.e., longest diameter. In this example, when TRTEST = "Lymph Node State" and TRORRES = "NON-PATHOLOGICAL", it indicates that the lymph node lesion was not pathological, i.e. the diameter has reduced below 10mm. The assessment of a lymph node is represented with TRTEST = "Lymph Node State" and TRORRES = "NON-PATHOLOGICAL" when that all target lymph node lesions have short axis less than 10mm or TRORRES = "PATHOLOGICAL" when at least one target lymph node tumor has short axis greater than or equal to 10mm. The image identifier is in TRREFID and matches a PRREFID in the PR Domain.

4.1.4 PR Domain Model

The pr.xpt table below shows the terminology used to implement RECIST 1.1 in the PR domain. This example shows the data for one subject collected at screening, week 6, week 12 and subsequent 8-week follow-up visits. The example shows an MRI of the head and neck (PRTRT = "MRI" and PRLOC = "HEAD AND NECK"), a CT scan of the chest (PRTRT = "CT SCAN" and PRLOC = "CHEST"), and medical photography of the skin of the trunk (PRTRT = "PHOTOGRAPHY" and PRLOC = "SKIN OF THE TRUNK") at each disease assessment timepoint. The image identifier is in PRREFID.

4.1.5 TD Domain Model

The td.xpt table below shows the terminology used to implement RECIST 1.1 in the TD domain. The TD domain is a trial design domain so it does not contain subject level data. The example shows three distinct disease-assessment schedule patterns. A single anchor date variable (TDANCVAR) provides the anchor date for each pattern. The offset variable (TDSTOFF) used in conjunction with the anchor date variable provides the start point of each pattern of assessments.

4.2 Example 2: RECIST 1.1 example to show investigator response (RS) data and the underlying tumor identification (TU), and tumor results (TR) data. 

This example shows the preferred representation of split (fragmented) and merged (coalesced) tumors. The tumor identifier is in TULNKID and matches TRLNKIDs in the TR Domain. 

4.2.1 RS Domain Model

The rs.xpt table below shows the terminology used to implement RECIST 1.1 in the RS domain. This example shows the data for one subject collected at the week 8 and subsequent 8-week follow-up visits. 

4.2.2 TU Domain Model

The tu.xpt table below shows the terminology used to implement RECIST 1.1 in the TU domain. This example shows the data for one subject collected at screening and subsequent visits. The example shows the preferred representation of split (fragmented) and merged (coalesced) tumors. This example also shows TUREFID used to represent the image identifier and TUSPID used to represent a sponsors internal tracking identifier.  

4.2.3 TR Domain Model

The tr.xpt table below shows the terminology used to implement RECIST 1.1 in the TR domain. This example shows the data for one subject collected at screening, week 6 and subsequent 8-week follow-up visits. The example shows the preferred representation of split (fragmented) and merged (coalesced) tumors. This preferred approach provides transparent with traceability with parent lesions. This example shows how to represent data on a single row when a target tumor becomes too small to measure. In terms of RECIST 1.1, the original results would be "TOO SMALL TO MEASURE" and the standard results (TRSTRESN and TRSTRESC) would be "5". In addition, the example represents a situations where a result was not provided because the image was obscured and the tumor was not assessable.

This examples shows that situation where the Investigator provided the summary values for Target lesions as a group (TRGRPID = "TARGET"). The TRTESTCD used for the assessments is "SUMDIAM". Note that the sponsor should not derived these values if they were not part of the data capture.

4.3 Example 3: RECIST 1.1 example to show investigator response (RS) data and the underlying tumor identification (TU), and tumor results (TR) data. This example also shows a case were progressive disease due to symptomatic deterioration was determined based on a clinical assessment by the investigator.  

4.3.1 RS Domain Model

The rs.xpt table below shows the terminology used to implement RECIST 1.1 in the RS domain. This example shows the data for one subject collected at week 8 and subsequent 8-week follow-up visits. The investigator also indicated that there was symptomatic deterioration indicating progression based on a clinical assessment that is not part of the response criteria (RSCAT = "PROTOCOL DEFINED RESPONSE CRITERIA"). The actual symptomatic deterioration is represented in the RSORRES value and the standardize representation (RSSTRESC) is "PD" (progressive disease). The Symptomatic Deterioration test (RSTESTCD = "SYMPTDTR") should only be used when this information is collected as part of the response forms.  Normally, it is expected that the subject continues having disease assessments until objective evidence of progression is documented. 

4.3.2 TU Domain Model

The tu.xpt table below shows the terminology used to implement RECIST 1.1 in the TU domain. This example shows the identification of target and non-target tumors at screening. The tumor identifier is in TULNKID and matches TRLNKIDs in the TR Domain.  

4.3.3 TR Domain Model

The tr.xpt table below shows the terminology used to implement RECIST 1.1 in the TR domain. This example also shows a case were progressive disease due to symptomatic deterioration was determined based on a clinical assessment by the investigator. In addition, the example represents a situations where a result was not provided because the scan was performed.

4.4 Example 4: RECIST 1.1 example to show investigator response (RS) data and the underlying tumor identification (TU), tumor results (TR) data. Example to show the use of the acceptance flag to identify records when multiple assessments are performed by independent assessors (Radiologist 1 and Radiologist 2) for the same timepoint.

4.4.1 RS Domain Model

The rs.xpt table below shows the terminology used to implement RECIST 1.1 in the RS domain. This example shows the data for one subject collected at week 6 and subsequent 8-week follow-up visits. 

This example shows the use of the acceptance flag (RSACPTFL) to identify records when multiple assessments are performed by independent assessors (Radiologist 1 and Radiologist 2) for the same timepoint, i.e., RSACPTFL indicates the "selected" response when more than read is performed. In some instances a vendor may only supply a single response record for the "selected" response either because there was adjudication or the vendor would select the appropriate response. This alternative approach would result in only the "selected" response records in the RS domain. It is not expected that the RSACPTFL flag would be populated by the sponsor. That type of record selection or censoring would by part of the analysis dataset.

This example also includes the situation where the Best Response assessment is provided by the data capture rather than derived.