From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors

Abstract

The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with (18)F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0.

Methods: PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors' experience, draft criteria were formulated for PET tumor response to treatment.

Results: Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has limitations in response assessments. For example, despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcoma, hepatomas, mesothelioma, and gastrointestinal stromal tumor. CT tumor density, contrast enhancement, or MRI characteristics appear more informative than size but are not yet routinely applied. RECIST criteria may show progression of tumor more slowly than WHO criteria. RECIST 1.1 criteria (assessing a maximum of 5 tumor foci, vs. 10 in RECIST) result in a higher complete response rate than the original RECIST criteria, at least in lymph nodes. Variability appears greater in assessing progression than in assessing response. Qualitative and quantitative approaches to (18)F-FDG PET response assessment have been applied and require a consistent PET methodology to allow quantitative assessments. Statistically significant changes in tumor standardized uptake value (SUV) occur in careful test-retest studies of high-SUV tumors, with a change of 20% in SUV of a region 1 cm or larger in diameter; however, medically relevant beneficial changes are often associated with a 30% or greater decline. The more extensive the therapy, the greater the decline in SUV with most effective treatments. Important components of the proposed PERCIST criteria include assessing normal reference tissue values in a 3-cm-diameter region of interest in the liver, using a consistent PET protocol, using a fixed small region of interest about 1 cm(3) in volume (1.2-cm diameter) in the most active region of metabolically active tumors to minimize statistical variability, assessing tumor size, treating SUV lean measurements in the 1 (up to 5 optional) most metabolically active tumor focus as a continuous variable, requiring a 30% decline in SUV for "response," and deferring to RECIST 1.1 in cases that do not have (18)F-FDG avidity or are technically unsuitable. Criteria to define progression of tumor-absent new lesions are uncertain but are proposed.

Conclusion: Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria have limitations, particularly in assessing the activity of newer cancer therapies that stabilize disease, whereas (18)F-FDG PET appears particularly valuable in such cases. The proposed PERCIST 1.0 criteria should serve as a starting point for use in clinical trials and in structured quantitative clinical reporting. Undoubtedly, subsequent revisions and enhancements will be required as validation studies are undertaken in varying diseases and treatments.

Figures

FIGURE 1

Kinetics of tumor cell kill and relation to PET. Line A represents brisk tumor response that would produce cure after only 4 cycles of chemotherapy. Line B represents minimum rate of tumor cell kill that will lead to cure in 6 cycles of treatment. Both lines would be associated with negative PET scan after 2 cycles of chemotherapy. In contrast, line C represents rate of tumor cell kill that would be associated with negative PET scan after 4–6 cycles but would not produce cure. Importantly, PET scan for line C would likely be positive after 3 cycles (27).

FIGURE 2

Number of papers that included use of tumor ROIs, as function of year of publication. Papers were identified by Medline search that queried for FDG AND SUV OR “standard uptake value” OR “standardized uptake value” OR “standardised uptake value”). Only human 18F-FDG oncology studies were included. ROI max refers to maximal pixel in tumor. ROI peak refers to small (typically 15 × 15 mm) fixed-size ROI centered on most metabolically active part of tumor. ROI isocontour refers to irregular ROI defined by isocontour set at, for example, some percentage of maximal pixel. ROI manual refers to manually drawn ROI. Only a subset of these papers describes response assessment studies.

FIGURE 3

Example calculation of liver background for normalization of SUL. Images are displayed from Advantage Workstation (GE Healthcare). A 3-cm-diameter 3-dimensional ROI (ROI 1) is placed on normal inferior right lobe of liver (arrowhead). Average SUL and SD in ROI are displayed (arrows). Liver background is calculated as follows: (1.5 × average SUL liver) + (2 × SD average SUL liver). For this example, (1.5 × 1.4) + (2 × 0.2) = 2.5. Therefore, tumor SUL peak should be >2.5 in order to apply PERCIST criteria for this example.

FIGURE 4

PET/CT images obtained before (1) and after (2) treatment of pancreatic carcinoma with experimental therapy targeting mammalian target of rapamycin. Note profound decline in SUL (∼41%) despite stable pancreatic mass anatomically (arrows). This decline represents metabolic partial response by PERCIST (41% decline in marker lesion at 2 wk after therapy). Not all metabolic PMRs are clinically relevant; relevance will depend on the specific treatment.

FIGURE 5

PET/CT image obtained before (1) and after (2) treatment of pancreatic carcinoma with experimental therapy targeting mammalian target of rapamycin. Glycolysis and apparent necrosis are profoundly reduced in intensely 18F-FDG–avid liver metastases. Although a reduction of more than 50% in SUL peak would suggest partial metabolic response, new lesion indicative of progressive metabolic disease is evident in left retroperitoneum (arrow).

FIGURE 6

(A) Patient with extensive non-Hodgkin lymphoma before treatment. Tumor with most intense 18F-FDG activity is in abdomen. Transverse images of easily measurable right axillary lymph node on CT are shown for convenience. (B) Commercial software tool (PET Volume Computed Assisted Reading; GE Healthcare) was used to localize foci of 18F-FDG uptake greater than mean liver SUL + 2 SDs of normal liver background (red). Manual intervention is required to separate normal 18F-FDG–avid foci, including brain, heart, and excreted urine, from relevant tumor. This semiautomated segmentation can be used to estimate total lesion glycolysis.