Evaluation and Assessment of the Radio-Peptide Treatment Efficacy

Abstract

The criteria settled for the evaluation of therapy response in solid tumors, i.e., those (a) of the World Health Organization (WHO, Miller et al. 1981), (b) the (RECIST criteria, Therasse et al. 2000), (c) the criteria of the European Association for the Study of the Liver (EASL, Bruix et al. 2001), (d) the new RECIST criteria (RECIST 1.1, Eisenhauer et al. 2009), and (e) the modified RECIST criteria (mRECIST, Lencioni and Llovet 2010) standardize regular measurement methods for converting image observations (CT or MRI) into a quantitative and statistically controllable framework that assesses the response of tumor to treatment. Eventhough the WHO criteria were first developed for radiography, CT, and MRI, they were modified into RECIST, RECICT 1.1 and mRECIST to formulate measurements more process-consistent. In consequence, a plethora of methods were developed to cover corresponding necessities derived from the several imaging technologies. Each method uses a pragmatically simplified technique that depends on the observer’s assessment of lesion limits. The chapter describes the most prominent response evaluation criteria not only used in neuroendocrine tumors but in every solid malignancy.

13.1 Introduction/Historical Corner

An early attempt to define the objective response of a tumor was made in the 1960s [1]. However, more systematically defined response assessment criteria were made by WHO in 1979, which resulted in the WHO handbook for reporting results of cancer treatments [2, 3]. Though the distinction of solid tumor was apparent, the response pattern within solid tumors was not obvious. In 1994, several organizations involved in clinical research proposed guidelines with the term RECIST 1.0 [4]; however, their applicability in different neoplasms was less than optimal [5]. With the development of newer imaging modalities (PET scan, MRI, nuclear imaging, etc.), it became clear that response assessment estimation does not fit for all solid tumors since RECIST criteria, apart from size, do not take into account changes in various tumor characteristics like tumor viability, metabolic activity, and tumor density characteristics directly associated with tumor response.

This resulted in various specialized groups to define more suitable and specific tumor response criteria (Table 13.1) according to corresponding necessities.

Table 13.1 Main response assessment criteria

13.2 Response Assessment

13.2.1 WHO Criteria

The WHO criteria aim to standardize the response assessment mainly in prospective randomized cancer clinical trials [2, 3]. According to them, the lesions are classified into two groups as measurable and non-measurable. The size of the lesion derives as a two-dimensional measure by multiplying the longest diameter by its perpendicular (vertical one) one. Complete response (CR), partial response (PR), no change (NC), and progressive disease (PD) are defined separately for measurable and non-measurable disease and bone metastases. The rules for determining overall response (OR) and the concept of duration of response (RD) and disease-free interval (DFI) are described.

However, the inadequate description of details of measurement rules and handling of exceptions lead to development of many modifications to WHO criteria in various trials and often to loss of comparability. As a sequence, WHO criteria are widely replaced by RECIST one (Table 13.2).

Table 13.2 Major differences between WHO and RECIST or RECIST 1.0 criteria

13.2.2 RECIST Criteria

In late 1994, a new concept was presented as RECIST 1.0 guidelines [4] which subsequently after revision was released in 2009 as version 1.1 [6]. Table 13.3 provides at a glance the important features and major changes of RECIST 1.0 to RECIST 1.1. They later gained popularity and nowadays are accepted by the majority of investigation authorities in the assessment of treatment outcomes in solid tumor.

Table 13.3 Major differences between RECIST 1.0 and RECIST 1.1 criteria

13.2.3 MD Anderson Cancer Center Criteria for Bone Metastases

According to WHO and RECIST criteria, bone metastases were initially considered non-measurable lesions, because metastases located in irregularly shaped bones are difficult to be measured. Since NETs do not or rarely metastasize in bone, it is clinically important to appropriately manage the osseous spread of the neuroendocrine disease. Thus, in 2004 Hamaoka et al. [12] proposed new response assessment criteria for response assessment of bone metastasis, known as the MD Anderson (MDA) criteria. These allow the use of various radiologic techniques with baseline images obtained by x-ray (XR), CT, MRI, or by some other modalities. The recommended duration for follow-up imaging is 2–6 months (Table 13.4).

Table 13.4 MD Anderson Cancer Center criteria

Vassiliou and Andreopoulos suggested MDA criteria may be improved by becoming more objective and accurate [18]. The implementation of CT to assess bone metastases would be very useful if the bone density in metastatic regions is measured in Hounsfield units (HU) after delineation of affected bone areas [18, 19].

13.2.4 Choi Criteria for Gastrointestinal Stromal Tumors (GISTs)

Choi et al. [10] in 2007 indicated that the RECIST 1.0 criteria underestimated the tumor response to imatinib in patients with metastatic GISTs; he aimed to develop criteria using CT scan as imaging modality as well as various tumor characteristics for the quantitative response evaluation in GISTs, beyond size measurement. In the meantime, EORTC criteria were available for response assessment using PET scan, but often the glucose uptake before treatment did not sufficiently detect them by FDG-PET (Table 13.5).

Table 13.5 Choi criteria for the evaluation of treatment response in GISTs

Choi criteria have been validated using time to progression endpoint. They are also used in assessing response in metastatic renal cell carcinoma [20], high-grade soft tissue sarcoma, solitary fibrous tumor [21], and hepatocellular carcinoma [22].

13.2.5 MacDonald and RANO Criteria for High-Grade Gliomas

In 1990, MacDonald et al. [14] published criteria for response assessment in high-grade gliomas, based primarily on contrast-enhanced computed tomography (CT) and the two-dimensional WHO oncology response criteria using enhancing tumor area including the use of corticosteroids and changes in the neurologic status of the patient.

However, it is obvious that there are significant limitations using only contrast-enhancing component of the tumor. Therefore, Wen et al. proposed new response criteria, commonly known as revised assessment in neuro-oncology (RANO) criteria [15].

RANO criteria provide (a) definitions and rules for standardization of imaging definitions, (b) number of lesions, and (c) definition of radiographic response. The sum of products of diameters (SPD) is calculated as products of maximal diameters, further adding them together. The responses are categorized as (a) contrast-enhancing lesions, (b) non-enhancing lesions, and (c) new lesions, based on thresholds defined in WHO criteria. The overall response (OR) is defined using response in enhancing lesions, non-enhancing lesions, new lesions, use of corticosteroids, and clinical status of the patient.

13.2.6 Response Assessment Criteria for Hepatocellular Carcinoma (HCC): EASL, mRECIST, and RECICL

The European Association for the Study of Liver (EASL) criteria is based on WHO criteria incorporating the concept of viable tumor tissue [11], quantifying the amount of enhancing (viable) tissue (Table 13.6).

Table 13.6 Major differences between EASL and mRECIST criteria

Similarly, the American Association for the Study of Liver Disease (AASLD) developed a set of guidelines named as modifying RECIST criteria (mRECIST) [7] and aimed to accommodate the concept of viable tumor tissue, too (Table 13.6).

In 2009, the Liver Cancer Study Group of Japan proposed revisions to Response Evaluation Criteria in Cancer of the Liver (RECICL) [17]. The criteria consider the tumor necrosis as a direct effect of treatment, whereas the dense accumulation of lipiodol is regarded as necrosis, too. Tumors are measured in two dimensions.

Furthermore, in 2009 alpha-fetoprotein (AFP) and AFP-L3 and des-gamma-carboxyl protein (DCP) were added for the overall treatment response [17, 23].

13.2.7 PET Response Criteria in Solid Tumors (PERCIST)

In PERCIST criteria [8], response to therapy is expressed as percentage change in the sum of lesions (SULs) between the pre- and posttreatment positron emission tomography (PET) scans. A complete metabolic response (CmR) is considered as a visual disappearance of all metabolically active tumors (Table 13.7). A partial metabolic response (PmR) is defined as a visual disappearance of more than a 30% (and a 0.8-unit decline) in SULs between the most intense lesion before and after treatment, not necessarily of the same lesion. A stable metabolic disease (SmD) is characterized as no substantial visual metabolic change between the pre- and posttreatment scans. A progressive metabolic disease (PmD) is classified as more than a 30% (and 0.8-unit) visual increase in SULs or new lesions between the pre- and posttreatment scans. Wahl et al. proposed another metric of progression [8] in the case of a greater than 75% increase in total lesion glycolysis.

Table 13.7 Major differences between RECIST 1.1 and PERCIST criteria

13.2.8 The European Organization for Research and Treatment of Cancer (EORTC) Criteria in Solid Tumors

Complete metabolic Response (CmR) would characterize a complete resolution of [¹⁸F]-FDG uptake within the tumor volume to be indistinguishable from surrounding normal tissue [16].

Partial metabolic response (PmR) would be defined as a reduction of a minimum of 15% ± 25% [¹⁸F]-FDG SUV in a tumor after one cycle of chemotherapy and greater than 25% after more than one treatment cycle.

Stable metabolic disease (SmD) is considered as an increase in tumor with [¹⁸F]-FDG SUV of less than 25% or a decrease of less than 15% and no visible increase in extent of [¹⁸F]-FDG tumor uptake (20% in the longest dimension).

Progressive metabolic disease (PmD) is classified as an increase in [¹⁸F]-FDG standardized uptake value (SUV) greater than 25% before and after treatment of the tumor defined on the baseline scan visible increase in the extent of [¹⁸F]-FDG tumor uptake (20% in the longest dimension) or the appearance of new [¹⁸F]-FDG uptake in metastatic lesions.

13.2.9 The Immune-Related Response Criteria (irRC) [9]

The immune-related response criteria arose out of observations that using the WHO or RECIST Criteria in immuno-oncology therapeutic schemes the delay (i.e., the time gap) between dosing (initial treatment) and the observed anti-tumor response failed to be taken into account. These observations first flagged in a key 2007 paper in the Journal of Immunotherapy [24], evolved into the immune-related response criteria (irRC), which was published in late 2009 in the journal Clinical Cancer Research [25]. The therapy results express four distinct response patterns: (a) immediate response (IR), durable stable disease (DSD), response after tumor burden increase, and response in the presence of new lesions. The first two patterns are conventional, whereas the latter two are novel and specifically recognized with immunotherapeutic agents [25].

Only measurable lesions are taken into consideration. Measures are taken bi-dimensionally for each lesion. To calculate total tumor burden, the sum of the perpendicular diameters of lesions at baseline is added to that of the new lesions.

Response categories under irRC are defined as immune-related complete response (irCR), immune-related partial response (irPR), immune-related stable disease (irSD), and immune-related progressive disease (irPD) using the same thresholds to distinguish between categories as defined in WHO criteria (Table 13.8).

Table 13.8 Major differences between WHO and iRC criteria

According to irRC, the appearance of new lesions alone does not constitute irPD if they do not add to the tumor burden by at least 25%. Patients with new lesions but an overall tumor burden decrease qualifying for partial response (≥50% decrease) or qualifying for stable disease (<50% decrease to >25% increase) are considered to have irPR or irSD, respectively [26].

13.3 The Southwest Oncology Group (SWOG) Criteria

In 1992, the Southwest Oncology Group (SWOG), in cooperation with the National Cancer Institute (NCI) in the USA and other major cooperative oncology groups, has participated in the development of new criteria for reporting the results of cancer clinical trial [13] (Table 13.9). Observing the three tabulated criteria and their differences, we can comprehend that a particular guideline may be useful in establishing uniformity of evaluation in a desired study population but may not be the best for that population during routine clinical practice. The comparison between them indicates that each of the guidelines has its own applicability and that no guideline can outweigh the other during routine clinical practice.

Table 13.9 Major differences between WHO, RECICT 1.0, and SWOG criteria