Search

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., (Copyright © 2016. Published by Elsevier Ltd.)

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., (Copyright © 2016. Published by Elsevier Ltd.)

Background: The main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan., Methods: Six hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350 mg/m(2) (or 300 mg/m(2) if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140 mg/m(2) (120 mg/m(2) if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ≥3 diarrhoea within 12 weeks of randomisation., Results: The proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=-6.3%, 95% confidence interval (CI) [-13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of -10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference., Interpretation: The pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC., Funding: The trial was funded by Cancer Research UK and supported by Amgen Pharma., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.

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-Hodgkin's 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.

Background: Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions., Future Work: A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.