Robert Ford

Evaluation of lymph nodes with RECIST 1.1

Lymph nodes are common sites of metastatic disease in many solid tumours. Unlike most metastases, lymph nodes are normal anatomic structures and as such, normal lymph nodes will have a measurable size. Additionally, the imaging literature recommends that lymph nodes be measured in the short axis, since the short axis measurement is a more reproducible measurement and predictive of malignancy. Therefore, the RECIST committee recommends that lymph nodes be measured in their short axis and proposes measurement values and rules for categorising lymph nodes as normal or pathologic; either target or non-target lesions. Data for the RECIST warehouse are presented to demonstrate the potential change in response assessment following these rules. These standardised lymph node guidelines are designed to be easy to implement, focus target lesion measurements on lesions that are likely to be metastatic and prevent false progressions due to minimal change in size.

iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.

Individual patient data analysis to assess modifications to the RECIST criteria.

BACKGROUND After the initial RECIST 1.0 were published in 2000, the criteria were widely implemented in the scientific oncology community. Since then, the RECIST working group has identified several issues to examine further. Two key issues that required careful, data-based assessment were the maximum number of lesions that should be assessed at each evaluation and the added value of requiring confirmation of response. METHODS To address these questions, data were obtained from 16 clinical trials in metastatic cancer, with patients enrolled between 1993 and 2005. A total of 6512 patients were included in the primary analysis dataset, accounting for over 18,000 potential target lesions. Nine percent of the included patients (n=585) had six or more reported target lesions. The response and progression outcomes in the database were calculated using an adjusted RECIST methodology with a maximum of 5 (or 3) target lesions with/without confirmation and this was compared to the original RECIST version 1.0 which required up to 10 target lesions plus confirmation of response. RESULTS Assessment of 5 lesions per patient led to a difference in best overall response assignment for an estimated 209 (3.2%) patients as compared to RECIST version 1.0. However, these changes did not affect the overall response rate. Progression-free survival was only minimally affected by measuring fewer lesions. In contrast, removing the requirement for response confirmation led to a significant increase in the numbers of patients classified as responders, resulting in a relative increase of approximately 19% in response rate. An algorithm using a maximum of three target lesions shows high concordance with the 10 lesions requirement in terms of response and TTP assignment. Concern that appropriate assessment of disease within an organ requires two lesions to be followed per organ suggests the approach of following two target lesions per organ, up to a maximum of five target lesions overall. Both strategies seem reasonable based on the data warehouse. The requirement of response confirmation in trials where this is a primary end-point is recommended to be maintained as its removal would substantially increase reported response rates.

Lessons learned from independent central review

Independent central review (ICR) is advocated by regulatory authorities as a means of independent verification of clinical trial end-points dependent on medical imaging, when the data from the trials may be submitted for licensing applications [Food and Drug Administration. United States food and drug administration guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Rockville, MD: US Department of Health and Human Services; 2007; Committee for Medicinal Products for Human Use. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) guideline on the evaluation of anticancer medicinal products in man. London, UK: European Medicines Agency; 2006; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-492 (oxaliplatin). Rockville, MD: US Department of Health and Human Services; 2002; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-923 (sorafenib tosylate). Rockville, MD: US Department of Health and Human Services; 2005; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-065 (ixabepilone). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-059 (lapatinib ditosylate). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Biologics Evaluation and Research. Approval package for BLA numbers 97-0260 and BLA Number 97-0244 (rituximab). Rockville, MD: US Department of Health and Human Services; 1997; United States Food and Drug Administration. FDA clinical review of BLA 98-0369 (Herceptin((R)) trastuzumab (rhuMAb HER2)). FDA Center for Biologics Evaluation and Research; 1998; United States Food and Drug Administration. FDA Briefing Document Oncology Drugs Advisory Committee meeting NDA 21801 (satraplatin). Rockville, MD: US Department of Health and Human Services; 2007; Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. JCO 2007(November):5210-7]. In addition, clinical trial sponsors have used ICR in Phase I-II studies to assist in critical pathway decisions including in-licensing of compounds [Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. JCO 2007(November):5180-6; Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. JCO 2007(August):3407-14; Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. JCO 2007(June):2171-7; Ghassan KA, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. JCO 2006(September):4293-300; Boué F, Gabarre J, GaBarre J, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkins lymphoma. JCO 2006(September):4123-8; Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. JCO 2006(July):3354-60; Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. JCO 2006(June):2502-12; Jaffer AA, Lee FC, Singh DA, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. JCO 2006(February):663-7; Bouché O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Fédération Francophone de Cancérologie Digestive Group Study-FFCD 9803. JCO 2004(November):4319-28]. This article will focus on the definition and purpose of ICR and the issues and lessons learned in the ICR setting primarily in Phase II and III oncology studies. This will include a discussion on discordance between local and central interpretations, consequences of ICR, reader discordance during the ICR, operational considerations and the need for specific imaging requirements as part of the study protocol.

Recommendations for the assessment of progression in randomised cancer treatment trials

Progression-free survival (PFS) is an increasingly important end-point in cancer drug development. However, several concerns exist regarding the use of PFS as a basis to compare treatments. Unlike survival, the exact time of progression is unknown, so progression times might be over-estimated (or under-estimated) and, consequently, bias may be introduced when comparing treatments. In addition, the assessment of progression is subject to measurement variability which may introduce error or bias. Ideally trials with PFS as the primary end-point should be randomised and, when feasible, double-blinded. All patients eligible for study should be evaluable for the primary end-point and thus, in general, have measurable disease at baseline. Appropriate definitions should be provided in the protocol and data collected on the case-report forms, if patients with only non-measurable disease are eligible and/or clinical, or symptomatic progression are to be considered progression events for analysis. Protocol defined assessments of disease burden should be obtained at intervals that are symmetrical between arms. Independent review of imaging may be of value in randomised phase II trials and phase III trials as an auditing tool to detect possible bias.

RECIST 1.1-Update and clarification : From the RECIST committee

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.

RECIST 1.1 – Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation.

Evaluation of 1D, 2D and 3D nodule size estimation by radiologists for spherical and non-spherical nodules through CT thoracic phantom imaging

The purpose of this work was to estimate bias in measuring the size of spherical and non-spherical lesions by radiologists using three sizing techniques under a variety of simulated lesion and reconstruction slice thickness conditions. We designed a reader study in which six radiologists estimated the size of 10 synthetic nodules of various sizes, shapes and densities embedded within a realistic anthropomorphic thorax phantom from CT scan data. In this manuscript we report preliminary results for the first four readers (Reader 1-4). Two repeat CT scans of the phantom containing each nodule were acquired using a Philips 16-slice scanner at a 0.8 and 5 mm slice thickness. The readers measured the sizes of all nodules for each of the 40 resulting scans (10 nodules x 2 slice thickness x 2 repeat scans) using three sizing techniques (1D longest in-slice dimension; 2D area from longest in-slice dimension and corresponding longest perpendicular dimension; 3D semi-automated volume) in each of 2 reading sessions. The normalized size was estimated for each sizing method and an inter-comparison of bias among methods was performed. The overall relative biases (standard deviation) of the 1D, 2D and 3D methods for the four readers subset (Readers 1-4) were -13.4 (20.3), -15.3 (28.4) and 4.8 (21.2) percentage points, respectively. The relative biases for the 3D volume sizing method was statistically lower than either the 1D or 2D method (p<0.001 for 1D vs. 3D and 2D vs. 3D).