The British Journal of Radiology, 74 (2001), 983–986 E 2001 The British Institute of Radiology
`
`Commentary
`The RECIST criteria: implications for diagnostic
`radiologists
`
`1A R PADHANI, MRCP, FRCR and 2L OLLIVIER, MD
`
`1The Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK and
`2Department of Radiology, Institut Curie, Paris 75005, France
`
`Monitoring response of tumours to treatment is
`an integral and increasingly important function of
`radiologists working in oncological
`imaging.
`Imaging studies play a pivotal, objective role in
`quantifying tumour response to a variety of phy-
`sical and pharmaceutical
`treatments. Objective
`tumour shrinkage has been widely adopted as a
`standard end-point to select new anti-cancer drugs
`for future study, as a prospective end-point for
`definitive clinical trials designed to estimate the
`benefit of treatment in a specific group of patients,
`and is widely used in everyday clinical practice to
`guide clinical decision-making. In the late 1970s
`it became apparent that a common language was
`necessary to report the results of cancer treat-
`ments
`in a consistent manner. Standardized
`criteria for measuring therapeutic response were
`adopted in 1981 but have been modified by
`various cancer organizations [1–3]. The World
`Health Organisation (WHO), the National Cancer
`Institute and the European Organisation for
`Research and Treatment of Cancer have recently
`adopted a new set of tumour response criteria
`(Response Evaluation Criteria in Solid Tumours
`(RECIST)) [4]. The RECIST criteria have been
`introduced to unify response assessment criteria,
`to define how to choose evaluable lesions and to
`enable the use of new imaging technologies (spiral
`CT and MRI). The RECIST documentation goes
`beyond lesion selection, measurement and assess-
`ment of response. It also makes specific recom-
`mendations on the usage of imaging techniques.
`The CT protocols are particularly detailed (imag-
`ing parameters for incremental and spiral machines,
`use of contrast enhancement and the presentation
`of images). The implications of this document are
`wide ranging and are likely to have cost and
`manpower implications for radiology departments
`in cancer treatment centres. This Commentary
`highlights these issues.
`The RECIST response criteria are largely
`based on a retrospective statistical evaluation
`
`Received 9 February 2001 and in revised form 20 April
`2001, accepted 14 May 2001.
`
`imaging data)
`(not original
`of measurements
`obtained
`in
`eight
`pharmaceutical-sponsored
`clinical trials where 569 patients were assessed
`for tumour response [5]. The data analysed were
`selected by their ‘‘availability’’ but did have a
`broad range of tumours and serial measurements,
`with outcomes recorded. The quality control of
`the measurements themselves is unknown. In
`an attempt
`to simplify tumour measurements,
`unidimensional and bidimensional evaluations were
`compared and the new criteria selected are chosen
`because of the link between change in diameter,
`product and volume of spherical lesions (Table 1).
`It has recently been noted that the two measure-
`ment methods continue to show good concordance
`for 4613 patients [6]. The new RECIST response
`criteria are designed to replace existing WHO
`criteria; the two sets of criteria are compared in
`Table 2.
`It is important to note that the RECIST criteria
`still rely on size change of
`lesions to make
`response assessments. RECIST acknowledges
`that tumour shrinkage may not be an appropriate
`end-point in the investigation of new cytostatic
`agents currently in phase 1 and 2 clinical trials [7].
`RECIST guidance defers the issues relating to
`functional tumour response and unique complex-
`ities of specific tumours or anatomical sites. There
`
`Table 1. Relationship between change in diameter,
`product and volume for spherical lesions [4]
`
`Response
`
`Disease
`progression
`
`Diameter
`(2r)
`
`Decrease
`30%
`50%
`Increase
`12%
`20%
`25%
`30%
`
`Product
`[(2r)2]
`
`Decrease
`50%
`75%
`Increase
`25%
`44%
`56%
`69%
`
`Volume
`(4/3pr3)
`
`Decrease
`65%
`87%
`Increase
`40%
`73%
`95%
`120%
`
`Shaded areas represent the response evaluation criteria in solid
`tumours (diameter) and WHO product criteria for change in
`tumour size to meet response and disease progression
`definitions.
`
`The British Journal of Radiology, November 2001
`
`983
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`

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`Table 2. Definition of best response according to WHO or RECIST criteria
`
`Best response
`
`WHO change in sum of products
`
`RECIST change in sum longest diameter
`
`Complete response
`(CR)
`
`Disappearance of all target lesions
`without any residual lesion;
`confirmed at 4 weeks
`
`Disappearance of all target lesions; confirmed
`at 4 weeks
`
`A R Padhani and L Ollivier
`
`Partial response
`(PR)
`
`Stable disease
`(SD)
`
`50% or more decrease in target lesions,
`without a 25% increase in any one
`target lesion; confirmed at 4 weeks
`
`At least 30% reduction in the sum of the longest
`diameter of target lesions, taking as reference
`the baseline study; confirmed at 4 weeks
`
`Neither PR or PD criteria are met
`
`Neither PR nor PD criteria are met, taking as
`reference the smallest sum of the longest
`diameter recorded since treatment started
`
`At least 20% increase in the sum of the longest
`diameter of target lesions, taking as reference the
`smallest sum longest diameter recorded since
`treatment started or appearance of new lesions
`
`Progressive disease
`(PD)
`
`25% or more increase in the size of
`measurable lesion or appearance
`of new lesions
`
`WHO, World Health Organisation [2]; RECIST, Response Evaluation Criteria in Solid Tumours [4].
`
`are many recognized limitations of size as a
`tumour response variable [8]. Size changes for
`both response and progression remain arbitrary.
`The measurement of lesions is laborious. Numer-
`ous errors occur when obtaining tumour measure-
`ments. These arise from observer variations of the
`estimated position of the boundary of lesions. The
`edges of irregular or infiltrating lesions are often
`difficult to define and, indeed, some tumours are
`impossible to measure. The difficulty of distin-
`guishing peritumoral fibrosis from tumour spread
`further
`confounds attempts at measurement.
`RECIST now excludes cystic or necrotic lesions
`when evaluating response. Measurement errors in
`estimating change in the size of small lesions can
`result in misclassification of response. Lavin and
`Flowerdew [9] showed that the WHO criteria of
`a 25% increase in the product of bidimensional
`diameters results in a one in four chance of
`declaring that progression has occurred when, in
`fact, the tumour is unchanged. So serious are
`these errors that ‘‘independent review panels’’ are
`often employed by pharmaceutical companies to
`standardize the reporting of tumour response in
`clinical trials. Independent review panel reports
`can disagree with ‘‘home radiologists’’ in 50% of
`cases, with major disagreements in up to 40% of
`cases [10]. The causes for such disagreements
`include variations in examination technique, lesion
`selection and siting of edges of target lesions. The
`need to tackle these discrepancies appears to be
`the primary motivation for revising the WHO
`criteria.
`The four categories of response have been
`retained to enable comparison of results of future
`treatments with those from the past. Although
`there are no major discrepancies in the meaning
`or the concept of the response categories, the
`definition of progressive disease has changed
`between the WHO and RECIST criteria. WHO
`criteria require that an increase of 25% should be
`
`the bidimensional
`in the product of
`present
`diameters to document disease progression. For
`a sphere, this would be an increase in tumour
`volume of approximately 40% (Table 1). The
`RECIST criteria require a 20% increase in the
`sum of the longest diameters, which is equivalent
`to a 73% increase in volume of a lesion similarly
`measured. The primary motivation for this change
`is to minimize the contribution of enlargement of
`small
`lesions [9]. As a result,
`it will be more
`difficult to categorize patients with progressive
`disease because greater volume increases will be
`required. The precision of measurement estimates
`has not been altered because there is no inherent
`biological meaning for an individual patient if
`there is a 30% or 40% change in tumour burden.
`At baseline,
`lesions are to be categorized as
`measurable or non-measurable. Measurable lesions
`are defined as those that can be measured accur-
`ately in at least one diameter, that is ¢20 mm
`using conventional imaging techniques (including
`incremental CT) or ¢10 mm using spiral CT
`equipment. Non-measurable lesions are discrete
`lesions with smaller dimensions. Non-measurable
`lesions also include bony metastases, leptomenin-
`geal disease, ascites, pleural/pericardial effusions,
`inflammatory breast cancer,
`lymphangitis carci-
`nomatosa, and heavily calcified and cystic/necrot-
`ic lesions. Interestingly, tumour lesions situated
`in a previously irradiated area may also not
`be considered as measurable disease. The term
`‘‘evaluable’’, which refers to lesions that can be
`viewed but
`cannot be measured, has been
`dropped. After establishing that measurable dis-
`ease exists, it is necessary to document ‘‘target’’
`and ‘‘non-target’’ lesions. Measurable lesions, up
`to a maximum of five lesions per organ and ten
`lesions in total, representative of all
`involved
`organs, should be identified as ‘‘target lesions’’.
`These target lesions should be selected on the
`basis of size and suitability for accurate repeated
`
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`The British Journal of Radiology, November 2001
`
`

`

`Commentary: RECIST criteria
`
`measurements. A sum of the longest diameter of
`all target lesions constitutes the ‘‘baseline sum
`longest diameter’’. Changes in sum longest diam-
`eter is to be used to categorize ‘‘target tumour
`response’’. Non-target lesions need not be meas-
`ured on follow-up studies but any change should
`be noted. Final response categorization should
`take into account changes in both target and non-
`target lesions as well as noting the presence or
`absence of new disease (Table 3). Note that for
`stable disease and progressive disease categories,
`the pre-treatment examination no longer serves as
`the baseline study. Instead, the reference study
`from which to make an evaluation is one where
`the smallest sum longest diameter was recorded
`(Table 2).
`Baseline evaluations are to be performed as
`close as possible to the beginning of treatment,
`but no more than 4 weeks before treatment starts.
`There is flexibility on the frequency of
`re-
`evaluation studies. However, it is recommended
`that follow-up every other cycle (every 6–8 weeks)
`should be performed in the context of phase 2
`studies where the beneficial effect of a therapy is
`unknown. An end of
`treatment examination
`enables overall
`treatment response assignment.
`In those patients with partial response (PR) or
`complete response (CR), confirmatory imaging is
`required at 4 weeks after the criteria for CR or
`PR have been met (this is also required for WHO
`criteria).
`
`Imaging recommendations
`
`The role of radiography in assessing tumour
`response is discounted, except
`for
`the chest
`radiograph. The consistency of the film-to-tube
`distance and projection has been stressed in this
`technique. Lesions adjacent to the chest wall or
`mediastinum should be preferentially assessed by
`CT or MRI. Radiographs cannot be used to
`assess bone lesions because bony metastases are
`classified as non-measurable lesions.
`
`Table 3. Overall responses for all possible combina-
`tions of tumour responses in target and non-target
`lesions with or without the appearance of new lesions [4]
`
`Target
`lesions
`
`Non-target
`lesions
`
`New lesions
`
`Overall
`response
`
`CR
`CR
`
`PR
`SD
`PD
`Any
`Any
`
`CR
`Incomplete
`response/SD
`Non-PD
`Non-PD
`Any
`PD
`Any
`
`No
`No
`
`No
`No
`Yes or no
`Yes or no
`Yes
`
`CR
`PR
`
`PR
`SD
`PD
`PD
`PD
`
`CR, complete response; PR, partial response; SD, stable
`disease; PD, progressive disease.
`
`Ultrasound should not be used routinely to
`assess response of lesions that are not superficial
`because the examination is operator independent.
`Ultrasound examinations cannot be reproduced
`for independent review at a later date because
`there is the implicit assumption that hard copy
`films truly reflect lesion dimensions. However,
`note that clinical palpation, endoscopic evaluation
`and even pathological evaluation are highly
`operator dependent. Ultrasound may be used as
`a possible alternative to clinical measurement,
`particularly for superficially palpable lymph nodes,
`subcutaneous lesions and thyroid nodules. There
`are no specific comments regarding ultrasound
`evaluation of breast cancer where presumably the
`palpating hand remains an acceptable method of
`evaluating response!
`MRI is accepted as a method for obtaining
`measurements provided that the same anatomical
`plane is used on subsequent examinations. If
`possible, the same imager should be used for
`serial evaluations. RECIST recognize that images
`produced by scanners at different field strengths
`will vary in quality. There are no specific sequence
`recommendations.
`When choosing measurable lesions on CT, the
`basic rule to be followed is that the minimum size
`should be no less than double the slice thickness.
`This is to minimize partial volume averaging
`effects that can lead to an underestimation of
`lesion size. The longest diameter of the target
`lesion should be obtained in the axial plane only.
`The type of CT machine is important with regard
`to selection of the minimum size of lesions. For
`spiral/helical CT scanners, the minimum size of
`a lesion may be 10 mm provided that a 10 mm
`collimation is used and reconstructions are
`performed at 5 mm intervals. For conventional,
`incremental CT scanners, the minimum size of
`lesions
`should be 20 mm with the use of
`contiguous 10 mm thick slices. In parts of the
`body where slice thicknesses used are less than
`10 mm (for example examinations on small sized
`patients), the minimum size of measurable lesions
`will differ, bearing in mind the rule above.
`The RECIST document recommends routine
`use of oral contrast medium. Many studies have
`shown that water is a better contrast medium
`when evaluating stomach and bowel
`lesions.
`Routine use of
`iv contrast medium is also
`recommended despite the fact that it may add
`little to a clinical study when objective response
`rate is based on measurable disease as the end-
`point. The RECIST guidance notes that some
`lesions become measurable only after administra-
`tion of iv contrast medium. Contrast medium can
`be avoided when evaluating discrete lung disease.
`Furthermore,
`‘‘an adequate volume of suitable
`contrast agents should be given so that metastases
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`The British Journal of Radiology, November 2001
`
`985
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`

`

`are demonstrated to their best effect and a
`consistent method of delivery is used on sub-
`sequent examinations for a given patient’’.
`Another key recommendation is that all images
`should be filmed, not just selected images of target
`lesions. Imaging departments with multislice CT
`scanners may thus incur increased film costs. This
`is intended to ensure that independent reviewers
`can satisfy themselves that no other co-existing
`abnormalities are present. All appropriate win-
`dow settings should be included, particularly in
`the thorax. It is recommended that lesions should
`be measured on the same window settings at each
`examination. It is not acceptable to measure a
`lesion at lung windows in one examination and
`soft tissue windows on another.
`The introduction of RECIST criteria is a faıˆt
`accompli. RECIST criteria will replace WHO
`criteria for the evaluation of objective tumour
`response in anti-cancer drug trials. These criteria
`will eventually play an increasing role in routine
`clinical practice. Response evaluation still uses
`size change as the primary tumour response
`variable. Categories of response have not been
`altered. What has changed is recognition of the
`importance of imaging and the method by which
`lesions are assessed (unidimensional measurement
`instead of bidimensional diameters). An overall
`response category will
`require assessment of
`changes in all categorized lesions with or without
`the appearance of new lesions. Larger volume
`changes will be required to document progressive
`disease. These RECIST criteria and imaging
`recommendations have important
`implications
`for imaging departments in cancer centres. Parti-
`cipation in clinical research is a time and resource
`intensive process. Research protocols demand
`resources in excess of normal clinical demands.
`Under RECIST, CT examinations will be
`required at increased frequency during treatment
`and an additional examination is required to
`confirm response in patients achieving PR or CR.
`The
`reduced use of plain radiographs and
`ultrasound with the emphasis on CT is further
`
`A R Padhani and L Ollivier
`
`likely to result in increased workloads for CT
`personnel. The need to measure and assess
`changes in multiple lesions in different categories,
`before an overall response assignment is made, is
`likely to have implications on the time spent by
`radiologists when evaluating patients participating
`in clinical trials. Radiologists should be enthu-
`siastic about
`formulating and participating in
`clinical research, otherwise non-trained staff will
`undertake these evaluations. An increased share
`of pharmaceutical resources (for equipment, time
`and manpower) is vital for successful implemen-
`tation of these recommendations.
`
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