Response Evaluation Criteria in Solid Tumors, World Health Organization, and Other Response Criteria

Monitoring the response of tumors to treatment has become an integral component of oncologic imaging. Imaging studies play a vital role in objective assessment by quantifying tumor response to a variety of physical and pharmaceutical treatments. Traditionally, therapeutic response has been assessed by conventional methods that involve serial tumor burden measurements according to the World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Computed tomography (CT) and magnetic resonance imaging (MRI) provide reliable and reproducible anatomic data to determine changes in tumor burden through treatment. However, the management of many tumors has extended beyond traditional chemotherapy and novel targeted therapies (such as antiangiogenic agents) have been introduced. With respect to targeted therapy, changes in tumor dimension may not be evident in the early course of treatment and measurement alone has been shown to have limitations. At the same time, to maximize the effectiveness of care, it is important to differentiate between responders and nonresponders as early as possible. Hence, monitoring effects from these expensive targeted therapies has introduced new expectations from imaging techniques. Conventional measurement-based methods are still widely used, but new techniques are being increasingly adopted. Emerging techniques such as positron emission tomography (PET or PET/CT) can be used to look at changes in tumor metabolism. There has been growing interest in the use of tumor viability measurement, dynamic contrast-enhanced imaging, or perfusion imaging to assess tumor vascular microenvironment and early antiangiogenic effects. Other advances in MRI such as diffusion weighted imaging (DWI) are also evolving as biomarkers of cellular integrity. Despite availability of various imaging techniques, it is challenging to determine the most appropriate image biomarker to serve as a surrogate end point of treatment response. An ideal imaging biomarker should be noninvasive, objectively quantitative, reproducible, readily available, validated, and easy to implement in the clinical setting. This chapter discusses various established and emerging and evolving imaging biomarkers, the criteria of response evaluation, and their challenges.

Response Criteria Based on Tumor Burden Measurement

World Health Organization Criteria

Response evaluation with diagnostic imaging has continuously evolved since the late 1970s. It has been generally accepted that a decrease in tumor size correlates with treatment effect. In view of this, the WHO first published a set of tumor response criteria in 1981, which was mainly used in clinical trials in which tumor response was the primary end point. The WHO criteria for tumor burden assessment were based on summing bidimensional, or two-dimensional (2D), measurements. The WHO criteria received wide acceptance, but were soon realized to have potential pitfalls such as no information on minimum lesion size or the number of lesions to be selected in patients with multiple lesions, the type of imaging modality that should be used, and lack of clarity among some definitions of response criteria. For example, a 25% increase in the product of 2D diameters (progressive disease) was defined by some investigators as increase in any one lesion and by others as increase in the sum of all selected lesions.

It was observed that many research trials initiated by pharmaceutical companies often modified WHO criteria to address areas that lacked clarity and also to accommodate new technologies (such as multidetector CT [MDCT]), and this led to variability and potential for overestimation or underestimation in clinical trial results.

Response Evaluation Criteria in Solid Tumors Criteria

RECIST 1.0

To address limitations of the WHO criteria, an International Working Committee was formed to standardize WHO criteria so that meaningful comparisons could be made among clinical trial studies. This led to the proposed RECIST criteria (version 1.0) in 2000. Important updates for RECIST criteria include adoption of unidimensional measurement (i.e., longest diameter) in RECIST versus bidimensional measurement in the WHO ( Figure 85-1 ), specification on tumor type that should be selected as tumor target, number of tumor targets in total and per organ to be chosen, broadening of the cutoff point defining progressive disease, and recommending the type of imaging that should be used. Even with introduction of RECIST 1.0, some important questions and issues remained unaddressed, such as assessment of lymph nodes, role of new imaging modalities such as PET/CT and MRI and if fewer than 10 lesions can be assessed without affecting the conclusion on response assessment. The RECIST Working Group subsequently revised the original criteria, and RECIST version 1.1 was released in 2008 ( Table 85-1 ).

TABLE 85-1

Key Features and Major Changes Between RECIST 1.1 and RECIST 1.0

Data from Eisenhauer EA: Response evaluation: beyond RECIST. Ann Oncol 18(Suppl 9):ix29–ix32, 2007; and Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247, 2009.

Key Features	RECIST 1.1	RECIST 1.0
Measurement method	Longest tumor diameter for extranodal lesions	Longest tumor diameter
Target lesion (measurable lesion) size	At least 10 mm on CT	10 mm on spiral and 20 mm on conventional CT
Number of target lesions	Total of 5 and up to 2 lesions per organ	Total of 10 target lesions and up to 5 per organ
Assessment of lymph nodes	Short axis measurement recorded. Target nodal lesion ≥15 mm, ≥10 mm, and ≤15 mm pathologic	Not specified
Clarification on disease progression	>20% increase in the sum of longest dimensions of target lesions (>5 mm absolute increase is required) and new lesions	>20% increase in the sum of target lesions (no absolute increase is required) and new lesions
Imaging modalities	Chest x-ray, CT, and MRI	CT, MRI, and FDG-PET (PET included for lesion detection only.) Chest x-ray can be used but not preferred

CT, Computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; PET, positron emission tomography.

RECIST 1.1

The guidelines defining tumor measurements by RECIST are simple, easy to apply, and quantitative. Optimization of image acquisition protocols at baseline and throughout follow-up examinations is essential for proper application of RECIST 1.1. Contrast-enhanced CT continues to be the most widely used modality. It is recommended to acquire CT images in the portal venous phase of contrast enhancement. For purposes of con­sistency, it is prudent to reconstruct 5-mm slices (or less) contiguously. To avoid partial volume averaging effects and inconsistent measurements of the same lesion (either target lesion or lymph node or non–lymph node) between serial examinations, the target lesion should be at least twice the slice thickness at baseline—that is, 10 mm if slice thickness is 5 mm. This principle is also applicable to MRI examinations. Measurements and comparisons should be performed on the same pulse sequence on serial studies. Measurement on a chest radiograph is acceptable if the lesion is surrounded by pulmonary parenchyma, but is not preferred owing to the lack of 3D.

Measurability of Tumor Burden

Target Lesion (Measurable Lesion)

Extranodal target lesions should meet the size criterion of 10 mm or greater in the longest dimension (see Figure 85-1 ). A lymph node is considered pathologically enlarged and measurable by RECIST 1.1 if the short axis measures 15 mm or greater on contrast-enhanced CT. At baseline and on subsequent posttreatment time points, the longest dimension of extranodal target lesions and short axis measurement of the node is used for assessing tumor burden and to monitor response. With respect to bone lesions, either lytic or mixed lytic-blastic bone lesions with soft tissue components can be considered measurable lesions as long as the soft tissue component meets the definition of measurability. In RECIST 1.1, blastic bone lesions are considered nonmeasurable. When both cystic and solid metastases are present, solid lesions are preferred as selectable target lesions. Lesions located in a previously irradiated area are not considered target lesions unless there is demonstrable progression in lesion size.

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