COMMON PITFALLS OF RECIST 1.1 APPLICATION IN CLINICAL TRIALS Authors: Iryna Teslenko MD, MS (Radiology Diagnostics); Maxim Belotserkovskiy MD, PhD, DrMedSc PSI CRO AG, Zug, Switzerland
Revised Response Evaluation Criteria in Solid Tumors (RECIST 1.1) came into effect in 2009 to address the issues and limitations of the previously applied version. We have been monitoring RECIST 1.1 application at clinical trial sites since 2009 and maintaining a database of RECIST 1.1 deviations and frequently asked questions. Analysis of the database showed that clinical investigators at different sites encounter similar difficulties in RECIST 1.1 interpretation and even make the same mistakes, which, if not timely identified and corrected, lead to increased variability of data across the trial sites and may affect efficacy endpoints. Common pitfalls of RECIST 1.1 application, which we`ve identified, are shown below. We grouped them into five categories for convenience. We developed and implemented RECIST 1.1 training program for the clinical trial sites and clinical operations staff, which in our opinion may help to increase the accuracy of the RECIST data extraction. CATEGORY 1 SELECTING TARGET LESIONS AT BASELINE
Our review has shown that the most frequent deviation from RECIST rules were incorrect selection of target lesions. Examples include: 1. Selection of more than two target lesions per organ in cases when only one or two organs were involved in the malignant process. 2. Addition of target lesions post baseline. 3. Selection of lesions with non-reproducible measurements, most often a lesion in a hollow movable, distensible organ, e.g. a bowel wall lesion, as target lesions. 4. Selection a pseudolesion as target. Examples of such pseudolesions are incidental adrenal masses, hemangiomas, benign ovarian tumours and cysts. 5. Selection of bone lesions that do not have a measurable soft-tissue component.
CATEGORY 2 REASSESSING TARGET LESIONS 1.
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CATEGORY 3 REASSESSING NON-TARGET LESIONS
This included premature declaration of progressive disease based on 20% increase in total sum but not triggering the required 5 mm absolute increase rule. Declaring PD based on 20% increase in a single lesion instead of total sum. Assessment of a timepoint response with reference to the immediately previous timepoint rather than to the guidelines recommended comparison with baseline and the nadir. Understanding of stable disease category as no change comparing to baseline, rather than a calculated category which numerical value shows neither sufficient increase to constitute progressive disease nor sufficient shrinkage to represent partial response. Trouble assessing target lesions’ response in situations where one of the lesions could not be visualized i.e. not visible on the scan at a timepoint because of bad image quality or being shadowed by another pathological process.
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These errors, in our database, were most often due to premature declaration of progressive disease based on change in size of non-target lesions by analogy with the target lesions assessment rules. Another common difficulty in this category pertains to interpretation of changes in volume or reappearance of a pleural effusion or ascites that was present at baseline. Reappearance or increase in volume of an effusion or ascites present at baseline does not represent progressive disease.
CATEGORY 4 ASSESSING FOR NEW LESIONS
The fourth category in our classification is perception of a new lesion by the reader. This, in our experience, is the most common reason of inter-reader variability in RECIST 1.1 assessment. Some readers do not acknowledge a new lesion if its size is smaller than the measurable lesion threshold. Although, according to RECIST 1.1 rules, any, even very small, unequivocal new lesion, independently of its size or location, indicates progressive disease.
CATEGORY 5 SUBSTANTIAL DEVIATIONS FROM THE SCANNING SCHEDULE
Overall, strict compliance to the scanning schedule is critical if one wants to obtain accurate study results. Critical deviations from the tumour assessment visit window outlined in the study protocol are considered as major protocol deviations because they may exclude the patient from the final statistical analysis and thus compromise the trial results. In situations when treatment cycle is delayed, for example due to toxicity, and treatment visits are re-scheduled, tumour assessment visits should continue in strict compliance with the initial schedule. In a similar way failure to perform end of treatment RECIST 1.1 assessment in case of symptomatic deterioration may threaten the trial results if occurs systematically at many sites. Symptomatic deterioration even being the reason for stopping therapy is not a descriptor of an objective tumour response, and every effort should be made to document objective progression even after discontinuation of treatment.
CASE REPORTS
CASE 1: A case of multiple deviations
CASE 2: An ambiguous case of new nodal lesions not considered as progressive disease
CASE 3: Response calculated based on non-target lesions measurements
CASE 4: Replacing a target lesion that became nonvisible with another one post baseline
CASE 5: Replacing a resolved target lesions post baseline
A patient had two lymph node lesions at baseline that corresponded to a measurable nodal lesions definition. The radiologist selected both lesions as target at the reassessment time point on week 32, two more lymph node lesions appeared. Instead of declaring progressive disease the radiologist added these new lesions as target thus violating several RECIST 1.1 rules at once, i.e. new lesion was not considered as progressive disease, target lesions were added postbaseline and more than two target lesions per organ were selected.
Radiologist described groups of slightly enlarged inguinal lymph nodes suspicious of metastatic involvement in a colorectal cancer patient at baseline. The lesions were smaller than 10 mm in their short axis, yet by their round shape they were most likely malignant. The lesions were described as non-target. According to RECIST 1.1 these lesions could not be included as pathological and should have been considered normal because of the size criterion even though they were suspicious of metastases. At week 16 follow-up scan, the lesions grew and became more than 10 mm in their short axis. Target lesions showed no change. If one wanted to strictly follow RECIST 1.1 rules, the patient had to be discontinued from the study due to new lesions appearance even though target lesions showed no progression.
In a patient with colorectal cancer and multiple metastases in liver and lungs the radiologist described all present lesions in great details including accurate measurements of all the target and nontarget lesions at every visit. The investigator performing RECIST 1.1 assessments at each visit tried to calculate response of both target and non-target lesions based on their measurements. In follow up, at week 32, the investigator erroneously determined PD because of one initially non-target lesion which increased in size by 20 % and showed more than 5 mm absolute increase. She made decision to discontinue the patient from the study based on an increase in a single non-target lesion that should have been assessed qualitatively only and never to be measured as per the criterion meant by the RECIST 1.1 for target lesions only.
Patient with SCLC had two target lesions selected in the right lung. At week 16 he developed collapsed lung segment that shadowed one of the target lesions on CT. In such a situation, the case should have been considered non-evaluable and the patient followed for progressive disease only. However, the investigator mistakenly decided to replace the target lesion that could not be anymore visualized with a different lesion in different location and continued response assessment. In general, it is not recommended to select target lesions in anatomical areas that could potentially become non-evaluable, like this lesion in a collapsed lung.
A patient with breast cancer had five target lesions at baseline. In the course of the treatment, one of the lesions resolved and the rest four lesions significantly decreased in size showing partial response. The investigator stopped documenting the resolved lesion among the target ones and added another lesion suitable to be target instead thus affecting response assessment
RECIST 1.1 TRAINING PROGRAM
We launched RECIST training program in 2006. The program has been tested over several years and modified to address the demands of the clinical sites and project teams. Current version of the training program comprises three levels.
LEVEL 1
LEVEL 2
LEVEL 3
Our in-house radiologist delivers RECIST 1.1 lectures as part of the annual corporate medical trainings program. We adjusted the content to meet the needs of the audience. We developed separate lectures targeted at the clinical research associates (CRAs), medical monitors and project managers. Training for CRAs contains some practical tips on how to check correctness of RECIST 1.1 application at clinical sites at the routine monitoring visit. Each lecture contains real-life examples, questions and answers session. All the attendees are supposed to pass a test after the lecture. In addition, CRAs have possibility to contact the in-house radiologist to get advice on RECIST 1.1 in the real time mode during their routine monitoring visits to clinical sites.
Medical Monitors train project teams and investigators in RECIST 1.1 and medical imaging requirements at the study setup phase during the CRA training and Investigator meeting. The protocol-specific training is adapted to the needs of the particular clinical study. For clinical studies with imaging based primary end point we recommend to have a separate medical imaging session delivered to the sites` radiologists at the Investigator Meeting. Ideally a radiologistconsultant should be involved starting from the protocol writing at the study setup phase to advise on the study design and medical imaging requirements.
Regular monitoring of the correctness of RECIST 1.1 usage during the routine monitoring visits to the sites and in the process of medical review of the clinical data allows timely detecting of mistakes and re-training of the investigators, site radiologists and if necessary CRAs. Medical Monitor is the one who is responsible for re-training however, there is possibility to involve in-house radiologist to address questions from the sites, deliver RECIST 1.1 lecture to the investigators and site radiologists remotely. The radiologist can also visit a clinical site to address the issues at a face-to-face meeting with the clinical team.
Regular educational RECIST 1.1 lectures
Project-specific RECIST 1.1 trainings
For cause re-training of the study sites and PSI CRAs We believe that involving a radiologist-consultant at all the phases of the clinical study to advice on the study design, to train the sites and to provide ad hoc consulting in the real time mode is necessary for successful study conduct. Address for correspondence:
[email protected]
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