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Revised Modified Response Evaluation Criteria in Solid Tumors for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1)

  • Samuel G. Armato III
    Correspondence
    Corresponding author. Address for correspondence: Samuel G. Armato III, PhD, Department of Radiology, The University of Chicago, 5841 South Maryland Ave., MC 2026, Chicago, Illinois 60637.
    Affiliations
    Department of Radiology, The University of Chicago, Chicago, Illinois
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  • Anna K. Nowak
    Affiliations
    Medical School and National Centre for Asbestos Related Diseases, University of Western Australia, Perth, Western Australia and Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
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Open ArchivePublished:May 09, 2018DOI:https://doi.org/10.1016/j.jtho.2018.04.034

      Abstract

      Introduction

      Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials.

      Methods

      The current de facto standard for the assessment of mesothelioma tumor response, “modified RECIST” (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented “modified RECIST 1.1 for mesothelioma” response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease.

      Results

      These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research.

      Conclusion

      Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.

      Keywords

      Introduction

      Tumor response based on computed tomography (CT) is governed by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors.
      These guidelines specify both an approach to tumor measurement and a set of response criteria that convert change in tumor measurements across serial CT scans into a response category. Modified RECIST (mRECIST) for mesothelioma, developed to address the limitations of RECIST when applied to the unique morphology and growth pattern of this disease, has become the standard response assessment paradigm for mesothelioma clinical trials.
      • Byrne M.J.
      • Nowak A.K.
      Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
      • Zalcman G.
      • Mazieres J.
      • Margery J.
      • et al.
      Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial.
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      • et al.
      Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.
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      Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study.
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      • Calabrò L.
      • et al.
      Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
      mRECIST specifically changed only the approach to tumor measurement from longest tumor diameter (which is ill-defined in mesothelioma) to tumor thickness perpendicular to the chest wall or mediastinum and limited the number of measured pleural sites to six. mRECIST explicitly adopted the same categorical response criteria established by RECIST. The paper from which mRECIST guidelines were extrapolated was primarily a research paper that sought to validate this novel thickness-based approach to tumor measurement.
      • Byrne M.J.
      • Nowak A.K.
      Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
      Other aspects of the RECIST guidelines were not addressed by mRECIST; therefore, they were intended by mRECIST to remain unchanged from RECIST when applied in the mesothelioma setting.
      mRECIST was developed more than 10 years ago and has not been revised in light of more recent research published or practical issues encountered. Also during this time, RECIST 1.1, a comprehensive update that incorporates new concepts such as revised minimum dimensions for lymphadenopathy and an approach to lesions that become non-measurable, was adopted.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      Mesothelioma response assessment would benefit from consideration of recommendations from RECIST 1.1 and other issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease. Experience and published literature now allow these and other issues to be addressed in this proposed mRECIST 1.1 for mesothelioma.

      RECIST Issues Not Explicitly Addressed by mRECIST for Mesothelioma

      Measurement Site Versus Lesion

      The unit of interest in RECIST and RECIST 1.1 is the lesion, which is characterized by a single unidimensional measurement of longest diameter. The RECIST guidelines contain concepts such as target lesion, measurable lesion, number of lesions, and minimum lesion size. Most solid tumors are discrete foci of tissue; pleural-based mesothelioma, however, grows as focal pleural thickening or a circumferential sheet around the lung. Consequently, a patient’s entire tumor burden could consist of a single continuous tumor mass extending around the lung and across numerous CT sections (slices). While such an extended tumor mass would represent a single lesion, it would be illogical to expect that a single measurement could capture the overall burden of this lesion — or that changes in a single measurement over time could represent lesion growth or regression. mRECIST introduced the concept of a measurement site, and mRECIST 1.1 now explicitly formalizes this concept for image-based mesothelioma tumor assessment. Rather than identifying individual measurable lesions and acquiring a single measurement for each such lesion, observers are to select a specified number of reliable measurable sites from which to acquire measurements within a scan, regardless of how many distinct, physical lesions these sites represent. Measurements of tumor thickness (constructed perpendicular to a tangent to the curve of the pleura at the outer tumor margin measurement endpoint) acquired from these measurement sites form the basis for mesothelioma tumor response assessment.

      Minimum Lesion Size

      The mRECIST mesothelioma tumor measurement protocol was validated (in the original mRECIST paper) by reassessing the response rate of 73 patients with malignant pleural mesothelioma who had participated in two previously reported phase II clinical trials.
      • Byrne M.J.
      • Nowak A.K.
      Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
      • Byrne M.J.
      • Davidson J.A.
      • Musk A.W.
      • et al.
      Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study.
      • Nowak A.K.
      • Byrne M.J.
      • Williamson R.
      • et al.
      A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma.
      Both trials predated publication of RECIST, so they were not informed by RECIST’s 10-mm threshold for minimum lesion size
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors.
      ; the design of these trials used 15 mm as the minimum lesion size for patient inclusion, a fact that simply was reported in the mRECIST paper. mRECIST did not establish a mesothelioma tumor thickness of 15 mm as the definition of minimally measurable disease. Although not explicitly reported, mRECIST incorporated the RECIST 10-mm definition of measurable disease when images from these earlier clinical trials were used to validate the measurement modifications introduced for mesothelioma and did not alter (or recommend altering) the threshold established by RECIST.
      RECIST states that “as a rule of thumb, the minimum size of the lesion should be no less than double the slice thickness”
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors.
      of the CT scan; therefore, “the minimum size of any given lesion at baseline may be 10 mm, provided the images are reconstructed contiguously at 5-mm intervals,”
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors.
      which was the usual section thickness at that time. Modern CT scanners are capable of section thicknesses less than 1 mm, with 2.5 mm or 3 mm currently the largest section thickness typically acceptable for clinical trials. Nevertheless, RECIST 1.1 “recommends that CT scans have a maximum slice thickness of 5 mm and the minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is <5 mm).”
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      The unique, nonspherical morphology of mesothelioma in which a sheet of pleural tumor typically extends across multiple axial CT sections negates the imaging-geometry–based recommendation that requires a 2:1 ratio between minimum lesion size and CT slice thickness — or at least this tumor morphology would support a recommendation that the 10-mm threshold be lowered for section thicknesses less than 5 mm. Another factor, however, must be considered in defining minimally measurable disease: observer variability in image-based measurements increases with smaller lesion size such that smaller lesions could exhibit measurement variability across serial scans and multiple observers that might erroneously yield classification as response or progression when, in fact, the lesion was stable.
      • Oxnard G.R.
      • Zhao B.
      • Sima C.S.
      • et al.
      Variability of lung tumor measurements on repeat computed tomography scans taken within 15 minutes.
      A recent study by Armato et al.
      • Armato III, S.G.
      • Nowak A.K.
      • Francis R.J.
      • Kocherginsky M.
      • Byrne M.J.
      Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions.
      investigated observer variability in mesothelioma tumor thickness measurements and reported findings suggesting “a reduction in minimally measurable lesion thickness from 10 mm to 5 or 7.5 mm might be warranted.”
      • Armato III, S.G.
      • Nowak A.K.
      • Francis R.J.
      • Kocherginsky M.
      • Byrne M.J.
      Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions.
      Because of differences in morphology, a 10-mm-thick mesothelioma tumor presents a greater tumor burden than a 10-mm-diameter spherical tumor, so imposing the same minimum size on mesothelioma as for other typically spherical tumors disadvantages patients and clinical trials through a greater baseline tumor burden (Fig. 1).
      • Armato III, S.G.
      • Nowak A.K.
      • Francis R.J.
      • Kocherginsky M.
      • Byrne M.J.
      Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions.
      • Oxnard G.R.
      • Armato III, S.G.
      • Kindler H.L.
      Modeling of mesothelioma growth demonstrates weaknesses of current response criteria.
      Furthermore, a requirement for all measurement sites to exceed a thickness of 10 mm may reduce the number of measurement sites available. Accordingly, mRECIST 1.1 recommends adoption of the more conservative findings from Armato et al.,
      • Armato III, S.G.
      • Nowak A.K.
      • Francis R.J.
      • Kocherginsky M.
      • Byrne M.J.
      Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions.
      decreasing the definition of minimally measurable disease for mesothelioma from 10 mm to 7 mm.
      Figure thumbnail gr1
      Figure 1A two-dimensional example shows that a 10-mm–diameter circle (representing a spherical tumor) has a much smaller area (volume) than a 10-mm–thick annulus (representing a rind of mesothelioma tumor).
      Reprinted with permission.
      • Armato III, S.G.
      • Nowak A.K.
      • Francis R.J.
      • Kocherginsky M.
      • Byrne M.J.
      Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions.
      A measurement site that initially exceeds the minimum size at baseline may exhibit a reduction in tumor thickness below the minimum size at follow-up. This situation is accommodated by RECIST 1.1 as follows: “If the lesion is believed to be present [on the follow-up scan] and is faintly seen but too small to measure, a default value of 5 mm should be assigned…,” but “…if the radiologist is able to provide an actual measure, that should be recorded, even if it is below 5 mm.”
      • Armato III, S.G.
      • Nowak A.K.
      • Francis R.J.
      • Kocherginsky M.
      • Byrne M.J.
      Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions.
      Disregarding issues of measurement variability, smaller mesothelioma tumor thicknesses should be more amenable to measurement than smaller spherical lesions because the more sheet-like structure of mesothelioma tumor reduces partial volume in the axial dimension, and a measurement site along mesothelioma tumor has one aspect that typically abuts normal structures. Accordingly, mRECIST 1.1 recommends follow-up measurement of all sites that reduce in size below the minimum measurable size, if such a measurement can be obtained (consistent with RECIST 1.1), and a default value of 2 mm (which deviates from RECIST 1.1) if tumor is present at a site but is too thin to measure.

      Modified RECIST Implementation Issues

      Measurement Process

      Measurement of mesothelioma tumor thickness on CT scans in accordance with mRECIST involves (1) selection of CT sections in which disease is most prominent, (2) identification of specific sites within these sections, and (3) measurement of tumor thickness at these sites; this third step has three components: (1) selecting a point along the outer tumor margin at which to initiate the measurement, (2) determining the direction that captures the most appropriate tumor dimension, and (3) locating the inner tumor margin along that direction.
      • Armato III, S.G.
      • Oxnard G.R.
      • MacMahon H.
      • et al.
      Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques.
      To facilitate this process, a computer interface should allow an observer to click on a pixel along the outer tumor margin within a selected CT section (to establish the endpoint of a line segment that will be created at this new measurement site), drag the cursor to stretch and orient a visible line segment as the other endpoint of the line segment tracks with the cursor, and release the cursor to fix the location of the other endpoint along the inner tumor margin thus creating a line segment that spans the tumor thickness (i.e., the tumor measurement at that site).
      Observers acquiring mesothelioma tumor thickness measurements in accordance with mRECIST have more degrees of freedom to consider than when measuring a spherical lesion in accordance with RECIST. Section selection, measurement site identification, the length of the constructed measurement line segment, and the angle the line segment makes with respect to the tumor boundary all must be considered. Two observers might construct line segments that extend from a given point along the outer tumor margin in the same direction but with different interpretations of inner tumor margin location; alternatively, observers might interpret inner tumor margin similarly but construct line segments that extend in different directions (Fig. 2).
      • Armato III, S.G.
      • Oxnard G.R.
      • MacMahon H.
      • et al.
      Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques.
      • Armato III, S.G.
      • Oxnard G.R.
      • Kocherginsky M.
      • Vogelzang N.J.
      • Kindler H.L.
      • MacMahon H.
      Evaluation of semi-automated measurements of mesothelioma tumor thickness on CT scans.
      Consistent implementation of these steps across observers (and across serial CT scans) is important for accurate tumor response assessment.
      Figure thumbnail gr2
      Figure 2Given the same point along the outer tumor margin (labeled “1”) from which to construct a line segment that spans tumor thickness at the defined measurement site, (A) four independent observers constructed measurement line segments oriented in nearly the same direction but with differences in the perceived inner margin of the tumor, and (B) the same observers interpreted the inner tumor margin consistently but constructed measurement line segments oriented over a wide range of angles. Both of these effects may impact the resulting tumor thickness measurements.
      Reprinted with permission.
      • Armato III, S.G.
      • Oxnard G.R.
      • MacMahon H.
      • et al.
      Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques.

      Measurement Consistency

      Consistency in measurement acquisition is essential but challenging. Inter- and intra-observer variability in image-based tumor measurement has been investigated extensively for many tumors, but variability in mesothelioma measurement has been addressed by few studies.
      • Armato III, S.G.
      • Nowak A.K.
      • Francis R.J.
      • Kocherginsky M.
      • Byrne M.J.
      Observer variability in mesothelioma tumor thickness measurements: defining minimally measurable lesions.
      • Armato III, S.G.
      • Oxnard G.R.
      • MacMahon H.
      • et al.
      Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques.
      • Sensakovic W.F.
      • Armato III, S.G.
      • Starkey A.
      • Ogarek J.L.
      Automated matching of temporally sequential CT sections.
      • Armato III, S.G.
      • Ogarek J.L.
      • Starkey A.
      • et al.
      Variability in mesothelioma tumor response classification.
      The first study to investigate variability in mesothelioma tumor thickness measurements reported 95% limits of agreement for relative interobserver difference that spanned a range of 30% when measuring the exact same measurement sites on the exact same CT scans
      • Armato III, S.G.
      • Oxnard G.R.
      • MacMahon H.
      • et al.
      Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques.
      ; this level of variability could lead to erroneous assessments of tumor response or progression across observers, even with no actual tumor change. Intra-observer variability was slightly better, with 95% limits of agreement for relative intra-observer difference that spanned a range of 27% for the same tumor measurement scenario. Variability likely would have been greater had observers individually been required to select measurement sites or had serial CT scans been evaluated.
      Another factor in measurement consistency is the angular orientation of the measurement. RECIST requires measurement of the longest diameter of a lesion at each time point although the longest diameter may not maintain the same orientation over time. The 95% limits of agreement in absolute interobserver mesothelioma measurement angle difference has been reported to span more than 25 degrees, which could contribute to measurement variability.
      • Armato III, S.G.
      • Oxnard G.R.
      • MacMahon H.
      • et al.
      Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques.
      Hence, according to mRECIST 1.1, once a baseline scan measurement of mesothelioma tumor thickness has been acquired at a selected measurement site, all subsequent tumor thickness measurements of that measurement site across time points should be oriented in the same direction as the baseline scan measurement.
      mRECIST 1.1 recommends that the same observer acquire measurements from all CT scans from a given patient using the same image display parameters (e.g., contrast/brightness settings). Observers acquiring measurements for mesothelioma should be familiar with the mRECIST 1.1 guidelines, should be experienced with measurement site selection and visual considerations for constructing measurements, and should be trained to use the software tool being implemented locally to acquire those measurements.
      Communicating image-based measurements in a standard, intuitive manner is important for the treating physician, for study personnel, and to ensure consistency over time. The visual presentation of measurements acquired at baseline (e.g., with measurement line segments shown superimposed on the tumor) during measurement of a follow-up scan yields significantly different measurements from those acquired when baseline scan measurements are simply documented in a report
      • Armato III, S.G.
      • Ogarek J.L.
      • Starkey A.
      • et al.
      Variability in mesothelioma tumor response classification.
      ; moreover, concordance in tumor response category among observers is improved. Potential ambiguities in measurement site location and placement of the measurement line segment at that site are greatly reduced when an annotated image is captured and made available at later time points (Fig. 3); modern image interpretation infrastructure should allow for such visualization. To improve measurement consistency across temporally sequential CT scans and achieve improved reliability of mesothelioma tumor response assessment, mRECIST 1.1 recommends that images of the baseline scan measurement line segments be stored and visually referenced when acquiring measurements from scans at subsequent time points.
      Figure thumbnail gr3
      Figure 3(A) Baseline scan measurements are shown as line segments superimposed on one section of a baseline CT scan. (B) Tumor thickness measurements acquired by an observer in the corresponding follow-up scan section based on (i) a written report of the baseline scan measurements only (black line segments) and (ii) visualization of the image shown in (A) (white line segments).
      Reprinted with permission.
      • Armato III, S.G.
      • Ogarek J.L.
      • Starkey A.
      • et al.
      Variability in mesothelioma tumor response classification.

      Measurement Site Selection

      RECIST 1.1 states that “when more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline,”
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      which amends the RECIST approach wherein a maximum of five lesions per organ and 10 lesions in total could be measured at baseline.
      • Therasse P.
      • Arbuck S.G.
      • Eisenhauer E.A.
      • et al.
      New guidelines to evaluate the response to treatment in solid tumors.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      RECIST 1.1 proposes selection of target lesions on the basis of size, representativeness of all involved organs, and potential for reproducibility of measurements across time points.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      mRECIST adopted a different approach by specifying selection of six measurement sites “in two positions at three separate levels on transverse cuts [sections] of CT scan” with the selected sections “at least 1 cm apart and related to anatomical landmarks in the thorax…to allow reproducible assessment at later time points.”
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      The need to specify selection of measurement sites highlights a key difference between mRECIST and RECIST: as previously noted, most solid tumors appear as discrete foci of tissue that themselves indicate the locations for measurement acquisition, whereas mesothelioma typically does not allow the enumeration of discrete lesions for measurement. Consequently, a standard approach to the identification of measurement sites is required.
      The published mRECIST could be interpreted as requiring exactly six pleural measurement sites. Although unclear in the published paper, mRECIST was actually validated on a dataset that included up to (rather than exactly) six pleural measurement sites. mRECIST 1.1 explicitly specifies selection of up to six pleural measurement sites at baseline (with no more than two sites per CT section and sites selected across no more than three sections each separated by at least 1 cm); each selected site must satisfy the mRECIST 1.1 criterion for minimally measurable disease. Measurement on axial CT sections displayed with a soft-tissue window is strongly preferred. All pleural tumor thickness measurements (along with measurements of non-pleural lesions and pathological lymph nodes, as appropriate [see below]) are summed to acquire summed measurement for the time point. Only sites selected at baseline are to be included in the summed tumor measurements on subsequent CT scans. Pleural effusion should never be included in measurement of tumor thickness.
      mRECIST indicates that measurement sites at baseline should be selected at the level of anatomic landmarks to facilitate identification of matched sites in subsequent scans, a concern that impacts measurement consistency across serial CT scans for response assessment and is especially relevant for a tumor such as mesothelioma that can change from differences in respiration and positioning. To achieve the greatest clinical relevance, however, measurement sites should be selected for the extent of tumor bulk observed or from a suspicion that tumor activity or the anatomic impact of the region is significant — considerations that will not necessarily align with anatomic landmarks. If baseline scan measurement line segments are viewed when acquiring measurements from follow-up scans as recommended by mRECIST 1.1, the preferred association of measurement sites with anatomic landmarks expressed by mRECIST can be relaxed. However, the RECIST 1.1 consideration of sites that “lend themselves to reproducible repeated measurements”
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      should be maintained in mRECIST 1.1. Consistent with mRECIST, and as a secondary consideration, measurement sites located (1) superior to the level of the left atrium are preferred to minimize the impact of inspiratory effort across time and (2) below the level of the aortic arch are preferred to minimize the impact of pleural curvature and volume averaging. If chest wall and mediastinal relationships have altered such that two measurement sites on a baseline scan section are not seen on the same section of a follow-up scan, subsequent measurements should use the section(s) that best corresponds with each baseline scan measurement site, even if measurements are acquired subsequently from adjacent sections.

      Bilateral Disease

      mRECIST does not address the possibility of bilateral disease. In bilateral disease, the pleura in both hemithoraces is considered a single organ (concordant with the approach of RECIST 1.1 for paired organs) so that the up-to-six pleural measurement sites may be distributed across both hemithoraces, as appropriate. Although, no more than two sites may be selected in any one CT section for any one hemithorax, section selection is to be considered for each hemithorax independently so that sites may be selected in up to three CT sections per hemithorax (subject to the constraint of no more than six selected pleural measurement sites in total). To mitigate the risk of measuring benign pleural disease, bilateral disease ideally should be confirmed by cytology or histology before inclusion as a pleural measurement site; however, this confirmation is not mandatory in the event of radiologic findings clearly consistent with malignant disease, such as evidence of progression on serial imaging.

      Non-Pleural Lesions

      mRECIST does not address non-pleural lesions. The presence of measurable non-pleural lesions is to be handled consistent with RECIST 1.1, namely, by the acquisition of longest-diameter measurements (10-mm minimum) from “a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs.”
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      Measurements from pleural sites are considered a contribution from one organ; therefore, the number of measurements attributed to the pleura for consistency with the RECIST 1.1 accounting will not exceed two (even if six pleural sites are selected). All measurements (pleural and non-pleural) are summed to acquire a single summed measurement for the time point. Fissural pleural disease is to be considered pleural (and represented by a thickness measurement perpendicular to a tangent to the pleura at the fissural measurement site), whereas lung parenchymal lesions are non-pleural. In accordance with RECIST 1.1, when measurable pleural disease is not present, at least one site of measurable non-pleural disease will constitute eligibility for clinical trials requiring measurable disease.

      Measurable But Non-Measured Pleural Disease and Non-Measurable Pleural Disease

      The up-to-six measurement sites are meant to be representative of global pleural thickening; however, numerous other potential measurement sites may be present but not measured. Moreover, other tumor regions may not meet the criteria for measurable disease. Under mRECIST 1.1, pleural disease (1) measurable but not used as a measurement site or (2) considered to be non-measurable (in either the ipsilateral or contralateral hemithorax) should be characterized by descriptive notations such as extensive pleural thickening or circumferential pleural thickening or tumor indistinguishable from diaphragm in base when site measurements do not reflect all areas of pleural involvement (Fig. 4); if only a small number of distinct pleural lesions is present in addition to those measured, these lesions might individually be identified as non-target lesions (a concept present in RECIST that was not adopted by mRECIST); however, it is not practical to separately identify individual pleural lesions that are contiguous or exceed some reasonable number, in which case a term such as extensive pleural nodularity would be appropriate.
      Figure thumbnail gr4
      Figure 4(A) Non-measured pleural thickening may be described as extensive circumferential pleural thickening with confluent fissural involvement. (B) Non-measured pleural thickening and nodularity may be described as irregular thickening and nodularity of mediastinal pleura.
      Despite the subjective nature of descriptive terms, their use can augment quantitative measurements of tumor thickness and provide an important characterization of disease when measurements are not possible. Furthermore, if the same reader interprets serial patient scans (or scans across all patients in a clinical trial), variability in the use of these terms should be reduced.

      Pathological Lymph Nodes

      mRECIST states that “nodal, subcutaneous and other bidimensionally measurable lesions” should be measured unidimensionally according to RECIST and that all unidimensional measurements should be summed to obtain the total measurement for a scan (implying that unidimensional measurements of any bidimensionally measurable lesions should be included with tumor thickness measurements). RECIST 1.1 provides enhanced specificity regarding lymph nodes and their designation as target or non-target lesions. According to RECIST 1.1, “pathological nodes which are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15 mm by CT scan,” and the short-axis length of such measurable, pathological lymph nodes contributes to the overall summed measurement of tumor burden. RECIST 1.1 further states that “all other pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered non-target lesions,” and their presence should be noted and followed. Lastly, “nodes that have a short axis <10 mm [at baseline] are considered non-pathological and should not be recorded or followed.”
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      • Schwartz L.H.
      • Bogaerts J.
      • Ford R.
      • et al.
      Evaluation of lymph nodes with RECIST 1.1.
      mRECIST 1.1 adopts the RECIST 1.1 treatment of lymph nodes and includes them in the summed measurement obtained from a CT scan, when appropriate, subject to the RECIST 1.1 accounting of measurements. mRECIST 1.1 thus aligns with evolving considerations of size criteria for what constitutes pathologic involvement of lymph nodes. Although lymph nodes in some areas of drainage from the pleura (e.g., intercostal lymph nodes, internal mammary lymph nodes, and diaphragmatic lymph nodes) are unlikely to be visualized at all unless they are involved, mRECIST 1.1 does not alter the criteria for specific lymph node stations.

      Validation of mRECIST

      The mRECIST paper reported validation in 73 patients from two prior phase II trials that used the WHO criteria for tumor response assessment.
      • Miller A.B.
      • Hogestraeten B.
      • Staquet M.
      • Winkler A.
      Reporting results of cancer treatment.
      The overall response rate of these patients based on mRECIST was the same as originally evaluated in the trials. Furthermore, when mRECIST was used to classify patients as responders or nonresponders, significant differences in survival and change in forced vital capacity between the two groups were observed. More recently, Labby et al.
      • Labby Z.E.
      • Armato III, S.G.
      • Dignam J.J.
      • Straus C.
      • Kindler H.L.
      • Nowak A.K.
      Lung volume measurements as a surrogate marker for patient response in malignant pleural mesothelioma.
      showed that change in tumor thickness measurements acquired in accordance with mRECIST was significantly and independently associated with poor prognosis in a cohort of 61 patients; response classification was not evaluated because this study considered tumor thickness as a continuous variable. In a study by de Perrot et al.
      • de Perrot M.
      • Dong Z.
      • Bradbury P.
      • et al.
      Impact of tumour thickness on survival after radical radiation and surgery in malignant pleural mesothelioma.
      mesothelioma thickness was an independent predictor of survival and disease-free survival in 65 consecutive patients undergoing surgery after radiotherapy. Similar findings were observed in a study of 472 patients as part of the International Association for the Study of Lung Cancer staging project, with absolute measurements of pleural thickness being strongly associated with survival.
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.

      Tumor Response Classification Criteria

      Complete response (CR) is disappearance of all pleural and non-pleural disease (including pleural thickening considered to represent tumor). CR must be confirmed at a follow-up scan at least 4 weeks later.
      Partial response (PR) is a summed measurement decrease by at least 30% from the baseline scan summed measurement, which must be confirmed at a subsequent follow-up scan at least 4 weeks later (at which time the summed measurement must not exceed 70% of the baseline scan summed measurement).
      Progressive disease (PD) is a summed measurement increase by at least 20% from the nadir of the summed measurements from all prior scans (including the baseline scan), even if the summed measurement is ≤70% of the baseline scan summed measurement; classification as PD also requires an absolute summed measurement increase of at least 5 mm over the nadir summed measurement per RECIST 1.1. Under mRECIST 1.1, an unequivocal new non-pleural lesion or an unequivocal new focus of pleural thickening that exceeds the minimum measurable size (and represents either a pleural tumor mass physically distinct from that associated with existing measurement sites or a region of a previously existing pleural tumor mass that would now unequivocally qualify as a measurement site) would be considered progressive disease. The assessment of unequivocal, however, requires careful review to ensure that the lesion was not present previously in an adjacent section (for example, the contraction of a hemithorax could alter the relationship between an area of pleural thickening and mediastinal landmarks).
      Stable disease (SD) is a decrease in the summed measurement that does not qualify as PR, or an increase in the summed measurement that does not qualify as PD.
      The tumor response classification criteria established by RECIST (and adopted by mRECIST) are based on mathematical extensions of the change in physical size of spherical objects. These criteria are not based on tumor biology, and the underlying assumption of this approach is that a 20% increase in the longest diameter of a lung nodule would have the same impact on a patient’s status, management, or prognosis as a 20% increase in the longest diameter of a liver lesion or any other solid, roughly spherical tumor. Mesothelioma, however, is grossly nonspherical. Geometric modeling by Oxnard et al.
      • Oxnard G.R.
      • Armato III, S.G.
      • Kindler H.L.
      Modeling of mesothelioma growth demonstrates weaknesses of current response criteria.
      showed that the RECIST response classification criteria are inconsistent with the morphology and growth patterns of idealized mesothelioma tumors. A study by Labby et al.
      • Labby Z.E.
      • Armato III, S.G.
      • Kindler H.L.
      • Dignam J.J.
      • Hasani A.
      • Nowak A.K.
      Optimization of response classification criteria for patients with malignant mesothelioma.
      empirically determined that the tumor response criteria for mesothelioma most highly correlated with patient survival (–64% for PR, +50% for PD) differed substantially from those of RECIST and were better aligned with the criteria derived from the simulations of Oxnard et al.
      • Oxnard G.R.
      • Armato III, S.G.
      • Kindler H.L.
      Modeling of mesothelioma growth demonstrates weaknesses of current response criteria.
      Despite these potential limitations of the RECIST tumor response criteria applied to mesothelioma, mRECIST 1.1 is unable to recommend a different set of criteria until prospective validation through a clinical trial occurs.

      Future Issues

      Volumetrics

      Tumor volume extraction from CT scans to capture directly tumor burden would, in principle, obviate the need for tumor measurement guidelines. Decisions on measurement site number and location, tumor thickness orientation, and site consistency across serial scans become obsolete when entire tumor volume is captured. The measurement of tumor volume, however, has challenges. Distinguishing mesothelioma from adjacent structures or concomitant abnormalities on CT can be highly subjective even if a computerized system is used to make the task more objective.
      • Corson N.
      • Sensakovic W.F.
      • Straus C.
      • Starkey A.
      • Armato III, S.G.
      Characterization of mesothelioma and tissues present in contrast-enhanced thoracic CT scans.
      Image-based tumor volume must incorporate the complete extent of tumor, including complex regions such as those near the diaphragm and those containing loculated effusion; such regions may be avoided when only individual measurement sites are required. Tumor volume measurement (even with computer assistance) requires radiologist expertise, and many trial sites currently have clinical investigators acquire tumor measurements.
      Mesothelioma tumor volume measurements show substantial variability because of factors including radiologist perception, image-acquisition parameters, patient set-up, and image analysis software
      • Gill R.R.
      • Naidich D.P.
      • Mitchell A.
      • et al.
      North American multicenter volumetric CT study for clinical staging of malignant pleural mesothelioma: feasibility and logistics of setting up a quantitative imaging study.
      ; these issues have been the subject of investigation in the more straightforward context of lung nodule volumetry.
      • Sullivan D.C.
      • Obuchowski N.A.
      • Kessler L.G.
      • et al.
      Metrology standards for quantitative imaging biomarkers.
      To further limit the reliability of mesothelioma tumor volume measurement in current practice, correlation between CT-based mesothelioma tumor volume and physical tumor bulk was found to be lower than expected.
      • Armato III, S.G.
      • Li P.
      • Husain A.N.
      • et al.
      Radiologic-pathologic correlation of mesothelioma tumor volume.
      Despite an association between mesothelioma tumor volume and survival, volumetric response criteria do not exist to translate changes in tumor volume into patient response categories or management decisions.
      • Labby Z.E.
      • Nowak A.K.
      • Dignam J.J.
      • Straus C.
      • Kindler H.L.
      • Armato III, S.G.
      Disease volumes as a marker for patient response in malignant pleural mesothelioma.
      • Pass H.I.
      • Temeck B.K.
      • Kranda K.
      • Steinberg S.M.
      • Feuerstein I.R.
      Preoperative tumor volume is associated with outcome in malignant pleural mesothelioma.
      • Gill R.R.
      • Richards W.G.
      • Yeap B.Y.
      • et al.
      Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume.
      • Liu F.
      • Zhao B.
      • Krug L.M.
      • et al.
      Assessment of therapy responses and prediction of survival in malignant pleural mesothelioma through computer-aided volumetric measurement on computed tomography scans.
      • Armato III, S.G.
      • Coolen J.
      • Nowak A.K.
      • et al.
      Imaging in pleural mesothelioma: a review of the 12th International Conference of the International Mesothelioma Interest Group.
      Furthermore, the utility of response criteria is less dependent on the precision of individual measurements and more focused on “finding consistent and easily applied methods to draw reproducible conclusions at the end of the trial.”
      • Verweij J.
      • Therasse P.
      • Eisenhauer E.
      RECIST working group. Cancer clinical trial outcomes: any progress in tumour-size assessment?.
      Hence, mRECIST 1.1 does not recommend incorporation of tumor volume into current response criteria other than as a research tool.

      T Staging

      Although a recent publication has proposed linear measurements of maximal tumor thickness at three points in the hemithorax as a metric for consideration in T staging, the purposes of T staging and response assessment are different and should not be confounded.
      • Nowak A.K.
      • Chansky K.
      • Rice D.C.
      • et al.
      The IASLC Mesothelioma Staging Project: proposals for revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for pleural mesothelioma.
      First, T staging should take place at diagnosis, whereas assessment of response is performed at any time that a new therapy or clinical trial is to be started. Second, the most appropriate locations for tumor measurement in the context of response may not capture the largest lesions (as proposed for T staging) but instead may be the most reproducible across multiple time points. Finally, the T staging proposal measures one site of maximal pleural thickness in each of the upper, middle, and lower zones of the affected hemithorax rather than summing six pleural measurements irrespective of zone. Nevertheless, the concept of measuring tumor thickness perpendicular to the chest wall or mediastinum as a surrogate for tumor bulk is related between T staging and response assessment.

      Immunotherapy

      Immunotherapy is currently under intense clinical trial study in mesothelioma, and benefit in this setting has been reported.
      • Alley E.W.
      • Lopez J.
      • Santoro A.
      • et al.
      Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial.
      Clinical trials in these agents are accompanied by challenges in the assessment of tumor response predominantly due to immune-related pseudoprogression, in which increased peritumoral inflammation may be visually indistinguishable from the tumor itself resulting in a perceived increase in tumor bulk on CT. Recently, consensus guidelines were published by the RECIST working group to modify RECIST 1.1 for application to immune-based therapeutics (iRECIST).
      • Seymour L.
      • Bogaerts J.
      • Perrone A.
      • et al.
      iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.
      The goal of iRECIST is to allow the identification of atypical responses, including delayed responses after pseudoprogression. The key principles of iRECIST require no changes to the measurement approach, concepts of objective tumor response, or the management of lymph nodes, but iRECIST does allow patients to continue on clinical trials through initial progression of baseline target lesions or the development of new lesions, and it introduces the concepts of unconfirmed progressive disease and confirmed progressive disease. Continued concurrent collection of RECIST 1.1 measurements (along with iRECIST measurements) is encouraged for clinical trials. As iRECIST does not alter any tumor response considerations that are unique to pleural mesothelioma, mRECIST 1.1 recommends adoption of the principles of iRECIST for immunotherapy clinical trials where pseudoprogression and delayed response may be a consideration. Hence, if continued treatment upon initial unconfirmed progressive disease is considered clinically safe and appropriate, subsequent confirmed progressive disease within 4 to 8 weeks would be required to confirm progression and cease study treatment. Specific guidance included in the study protocol should incorporate the principles of mRECIST 1.1 (including selection of measurement sites, number of sites, and measurable disease guidance) together with the principles of iRECIST as applied to progressive disease.

      Positron-Emission Tomography – CT for Response Assessment

      Although 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) and 18F-FDG-PET/CT have been studied for the assessment of response to therapy in mesothelioma, the use of this imaging modality in response assessment and as a surrogate for patient benefit in clinical trials has not been validated.
      • Ceresoli G.L.
      • Chiti A.
      • Zucali P.A.
      • et al.
      Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose.
      • Francis R.J.
      • Byrne M.J.
      • van der Schaaf A.A.
      • et al.
      Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans.
      • Veit-Haibach P.
      • Schaefer N.G.
      • Steinert H.C.
      • Soyka J.D.
      • Seifert B.
      • Stahel R.A.
      Combined FDG-PET/CT in response evaluation of malignant pleural mesothelioma.
      Furthermore, the presence of an inflammatory response in the context of prior pleurodesis or in the postoperative setting leads to difficulty in interpreting changes over time on FDG-PET-CT.
      • Genestreti G.
      • Moretti A.
      • Piciucchi S.
      • et al.
      FDG PET/CT response evaluation in malignant pleural mesothelioma patients treated with talc pleurodesis and chemotherapy.
      • Kwek B.H.
      • Aquino S.L.
      • Fischman A.J.
      Fluorodeoxyglucose positron emission tomography and CT after talc pleurodesis.
      • Nowak A.K.
      • Francis R.J.
      • Phillips M.J.
      • et al.
      A novel prognostic model for malignant mesothelioma incorporating quantitative FDG-PET imaging with clinical parameters.
      Currently, the use of FDG-PET in the assessment of treatment response in clinical trials is not recommended.

      Conclusion

      In summary, these proposed mRECIST 1.1 guidelines for mesothelioma tumor response collate and apply research in this field published since the development of mRECIST, align mRECIST with RECIST 1.1, address those aspects of tumor measurement that were not well addressed in the initial research paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research (Supplementary Data 1). Substantive changes have only been proposed where supported by published data; clarification of ambiguity and alignment with RECIST 1.1 are not considered substantive changes. mRECIST 1.1 includes proposed modifications for immunotherapy trials that incorporate the principles of iRECIST without altering key considerations in the approach to pleural mesothelioma measurement (Supplementary Data 2). Suggested response assessment guidelines for inclusion in clinical trial protocols have been developed. Adoption of mRECIST 1.1 for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.

      Acknowledgments

      This article has been endorsed by the Board of the International Mesothelioma Interest Group (iMig). Dr. Armato is a consultant for Aduro Biotech, Inc. The authors thank Chris Straus, MD, Heber MacMahon, MD, and Ritu Gill, MD, for useful discussions.

      Supplementary Data

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      Linked Article

      • Erratum
        Journal of Thoracic OncologyVol. 14Issue 3
        • Preview
          Erratum to: Armato SG III, Nowak AK. Revised modified Response Evaluation Criteria in Solid Tumors for assessment of response in malignant pleural mesothelioma (version 1.1). J Thorac Oncol. 2018;13(7):1012-1021.
        • Full-Text
        • PDF
        Open Archive
      • Revised Modified RECIST Criteria in Malignant Pleural Mesothelioma (Version 1.1): A Step Forward in a Long Race
        Journal of Thoracic OncologyVol. 13Issue 7
        • Preview
          Response assessment in mesothelioma using the Response Evaluation Criteria in Solid Tumors (RECIST) continues to be challenging, with higher disagreement between investigators that with other solid tumors. The modified RECIST1 system that was published in 2004 enabled more accurate measurements of the pleural rind by implementing six perpendicular chest wall measurements from three separate sections of the pleural tumor. Even though this was an improvement over RECIST, high variability and imprecision in measurements and adherence to the correct methodology continues to affect response assessment.
        • Full-Text
        • PDF
        Open Archive