This paper describes a consensus guideline, rather than a formal literature review. However, a database search was done using PubMed in August, 2016, with the following search terms: “immune response criteria” (limited to cancer, clinical trials, and publications in English language; 234 citations), “irRC” (23 citations), and “pseudoprogression” (limited to cancer, clinical trials, and pubications in English language; 39 citations).
ReviewiRECIST: guidelines for response criteria for use in trials testing immunotherapeutics
Introduction
Changes in tumour burden (termed response) are often used as surrogates of survival or quality of life;1 consequently, validated and consistent criteria for defining response to treatment are crucial. In 2000, the Response Evaluation Criteria in Solid Tumours (RECIST) working group simplified the 1981 WHO response criteria2 after validation in a large data warehouse.3 In 2009, RECIST was refined to RECIST version 1.1.4 The RECIST working group ensures that RECIST undergoes continuous testing, validation, and updates.5, 6, 7
Immune modulators are one of the most important classes of new anticancer therapeutics.8, 9, 10 Cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) pathways are the most intensively studied,11, 12, 13, 14, 15, 16, 17 and drugs that are active in these pathways have, since 2011, received marketing authorisation (for some drugs the authorisation is conditional, pending the completion of other studies) for melanoma, lung, bladder, renal, and head and neck cancer.18, 19, 20, 21, 22, 23 The novel mechanism of action of these drugs, with immune and T-cell activation, is postulated to lead to unusual patterns of response that resemble tumour flare but are more pronounced and more frequent than previously described responses. In early trials of immune-based therapeutics in melanoma, investigators described unique response patterns, termed pseudoprogression. Some patients whose disease met the criteria for disease progression based on traditional response criteria such as RECIST (an increase in the sum of measures of target lesions, unequivocal increase in non-target disease, or the appearance of new lesions) were noted to have late but deep and durable responses.24, 25, 26, 27, 28 In 2009, modified response criteria based on WHO criteria (which include the collection of bidimensional measurements of target lesions) were proposed—the immune-related response criteria (irRC).29 The major modification involved the inclusion of the measurements of new target lesions (each must be at least 5 × 5 mm in size; with a maximum of ten visceral lesions in total, up to five new lesions per organ, and five new cutaneous lesions) into disease assessments. In 2013, researchers published revised irRC using unidimensional measurements based on the original RECIST.30 Subsequent recommendations, some published in abstract form, seem to incorporate RECIST 1.1 recommendations.31, 32, 33 These recommendations are often referred to as irRECIST, but have not always been consistently applied, leading to concerns about the comparability of data and results across trials, difficulty with pooling databases, and poor clarity regarding whether new lesions were measured, and if so, how many were captured, and whether measures were incorporated into tumour burden. Recent trials (since 2010) have generally used RECIST-based immune criteria to assess responses to immunotherapies.
Because of the need to standardise and validate response criteria, the RECIST working group prospectively planned to create a warehouse of data from trials of immunotherapeutics to test and validate RECIST 1.1 and suggest modifications if required. During the planning and initial collection of the immunotherapeutic warehouse, it was apparent that most trials testing these drugs have typically used RECIST 1.1 to define the primary and secondary efficacy-based endpoints, and reserved irRC or their modified definition of RECIST for exploratory endpoints.31, 32 Additionally, substantial variability in which criteria were used was seen across clinical trials within pharmaceutical companies and cooperative groups, leading to serious concerns about interpretation of pooled datasets. Finally, most trials that used immune-modified criteria used independent imaging review by a commercial entity for those criteria, rather than investigator assessments. We think that response criteria should be applicable across all cancer clinical trials, including those done in the academic sector, where costly independent review is not feasible.
On the basis of these observations, the RECIST working group decided to develop a guideline for the use of a modified RECIST to ensure consistent design and data collection that would facilitate the ongoing collection of clinical trial data and ultimate validation, if indicated, of a modified RECIST 1.1 for immune-based therapeutics (termed iRECIST). These guidelines are not intended to define or guide clinical practice or treatment decisions, but rather to provide a consistent framework for the management of data collected in clinical trials of immune-based therapies. Treatment decisions rest with the patient and their health-care team.
Section snippets
Terminology
iRECIST is based on RECIST 1.1. Responses assigned using iRECIST have a prefix of “i” (ie, immune)—eg, “immune” complete response (iCR) or partial response (iPR), and unconfirmed progressive disease (iUPD) or confirmed progressive disease (iCPD) to differentiate them from responses assigned using RECIST 1.1. Similar nomenclature is used for stable disease (iSD). New lesions are assessed and subcategorised into those that qualify as target lesions (new lesion, target) or non-target lesions (new
Development of the guideline
The RECIST working group formed a subcommittee and held a series of conference calls and face-to-face meetings in 2015 and 2016 to discuss plans for the development and validation of iRECIST (figure 1) and to review existing approaches to assess response in immune modulator trials, and also to identify points of consensus and items that needed further discussion. Members of the subcommittee included clinical, statistical, and imaging experts in methodology and immunotherapy, representatives
iRECIST
The continued use of RECIST 1.1 is recommended to define whether tumour lesions, including lymph nodes, are measurable or non-measurable, as well as for the management of bone lesions, cystic lesions, and lesions with previous local treatment (eg, radiotherapy; table 1). Similarly, no changes have been made to the recommendations regarding the method of measurement, although clinical examination and chest radiograph are rarely used, with the availability of more modern imaging techniques (eg,
Discussion: next steps and validation
Immunotherapeutics are a major advance in the treatment of an escalating number of cancers. The increasing testing and use of these drugs in multiple clinical settings, including adjuvant, first, second, and subsequent lines of therapy will require the use of progression-based endpoints. RECIST 1.1 might not always adequately capture the unique patterns of response that have been well described in clinical trials of these drugs in a low proportion of patients, typically reported as 10% or less,
Search strategy and selection criteria
For more on the RECIST working group see //www.eortc.org/recist/
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