In 2000, the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) was first published, setting forth rules defining when cancer patients improve (respond), worsen (progression) or stay the same (stable) during treatment.

  The criteria emerged from an international collaboration that included the European Organization for Research and Treatment of Cancer, the National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group. Although originally developed for clinical use, RECIST is now employed in the majority of clinical trials evaluating cancer treatments for objective response or progression free survival analysis in solid tumors. 

The first formal revision of the criteria (RECIST 1.1) was published in January 2009 by a consortium of academic, government, and industry stakeholders known as the RECIST Working Group to address shortcomings of the original.

  The updated version, similar to RECIST 1.0, remains grounded in the anatomical assessment of disease and gauges patient response based on unidimensional measures of tumor lesions in combination with a qualitative assessment of nonmeasurable lesions and new lesions.

  But RECIST 1.1 better reflects the realities of clinical practice, the growing importance of disease progression as a primary endpoint, and the pivotal role of target lesions in gauging tumor response. Further, RECIST 1.1 opens up new doors for sponsors in terms of patient recruitment and label expansion and could potentially help them achieve some spending and scheduling efficiencies. 

This article describes the new RECIST criteria and compares them to the original ones. RECIST 1.1, while meaningful and straightforward, can be difficult to implement outside of leading academic research centers without significant commitment to physician training. The necessity of using RECIST 1.1 in parallel with the original RECIST, potentially for years to come, could create general confusion at investigative sites regarding what structures to measure and how to make the determinations. The pros and cons of using RECIST 1.1 are dependent not only on specifics of individual studies and the indication, but also on sponsors comfort in blazing the regulatory trail with an untested methodology for evaluating efficacy. 

There are a number of significant changes in RECIST 1.1 compared to 1.0 (see Table 1). One of the most challenging is the measurement of lymph nodes. The RECIST Working Group precisely defines when nodes are pathologic versus normal and healthy. Under the original guidelines, patients with remaining small but measurable nodes would fail to meet the criteria for "complete response" even if all non-nodal target lesions had disappeared. The new guidelines stipulate 10 mm as the cutoff point in differentiating between a healthy and a pathologic node. 

RECIST 1.1 specifies that target nodes be measured in the short axis, perpendicular to the longest diameter. This approach is deemed more reproducible and predictive of malignancy than the customary approach of measuring in the long axis.

Significantly, the new guidelines allow sponsors to enroll patients into oncology studies who have nonmeasurable disease only when the primary endpoint is progression-related. A good example and currently popular research indication for this is gastric cancer. Primary tumors still in place or recurrent in the gastric wall must be assessed qualitatively because the gastric wall moves and changes appearance, making it impossible to reliably and reproducibly measure those lesions. 

RECIST 1.1 effectively enlarges the universe of patients that can participate in studies, potentially speeding enrollment, shortening timelines, and increasing product marketability to new indications. The caveat is the creation of potential subpopulations, including those with and those without measurable disease. Sponsors are left to resolve the puzzle of how to make statistically sound comparisons between qualitative and quantitative assessments of tumor response. 

Added language in RECIST 1.1 clarifies that the finding of a new lesion should be unequivocal and not attributable to something other than disease, such as differences in scanning technique or healing of a pre-existing lesion. This is particularly important if lesions show partial or complete response to treatment. For example, necrosis of a liver lesion may be reported on a computed tomography (CT) scan report as a "new" cystic lesion, which it is not. 

The new criteria also de-emphasize the importance of nontarget lesions. Target lesions, assigned at baseline, should tell the whole story. Overall response tables offered by RECIST 1.1 (see Table 2) suggest that what happens to them more often than not determines whether a patient is deemed to have improved or their disease has stabilized, even when the nontargeted lesions are not evaluable. 

The elevated status of target lesions could add a degree of freedom to image scheduling. RECIST 1.1 acknowledges that imaging of nontarget lesions is unnecessary at every protocol-specified time point for a declaration of partial response or stable disease. Potentially, this could translate into trials that are less costly as well as more palatable to physicians worried about radiation exposure. 

In the new guidelines, several changes have been made to the criteria as to when confirmatory measurement is required. RECIST 1.0 stipulates that a patient's initial response to treatment must be documented a second time, no sooner than four weeks later. RECIST 1.1 adds that the response need not be confirmed in randomized trials where disease progression is the primary endpoint. However, sponsors might still want to consider independent review if disease progression is not clearly unequivocal to reduce the odds of patients being removed from a trial prematurely or inappropriately. Sponsors may also be interested in secondary response-related endpoints for which confirmatory scans or regulatory endorsement of the protocol design would be advisable. 

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is embraced for the first time by RECIST 1.1, albeit as a functional imaging modality supporting CT scanning rather than independently driving the determination of disease progression. The implication is that FDG-PET is most appropriate for exploratory purposes in early phases on small numbers of patients at a few select sites. Its time has not yet come for use in late-phase studies involving multiple patients and sites due to limited global availability and, more importantly, insufficient standardization. SNM (formerly the Society of Nuclear Medicine) is currently working to reduce variability across nuclear medicine sites worldwide by defining image acquisition and analysis standards.

The selection of five (maximum two per organ) rather than 10 (maximum five per organ) target lesions at baseline is one of the most talked about revisions to RECIST but is noteworthy only because it better mirrors clinical practice. Tumor response to treatment is nearly always assessed on fewer than 10 target lesions. Patients may have no more than five or six lesions available to measure. Data analysis has also shown that study outcomes are unaffected when only five lesions were selected as targets.

  Similarly, RECIST 1.1 establishes 5mm as the threshold value that should be assigned to all target lesions or lymph nodes that are "too small to measure." A 2mm difference to a tiny 4mm lesion is a 50% change, but truly, these 2mm do not accurately reflect a treatment effect, even if those changes could be accurately measured. 

Discussing the remaining revisions to RECIST criteria is beyond the scope of this article. These include:  				

The removal of bone and cystic lesions from the list of nonmeasurable lesions, enlarging the definition of complete response (to encompass lymph nodes)

Recommendations for measuring lesions that split or coalesce. RECIST 1.1 also specifically addresses how lesion reappearance should impact a prior conclusion about patient response to treatment.   

Although RECIST 1.1 has several potentially important advantages over the original version, implementing the new criteria could be challenging for both sites and sponsors. Perhaps most concerning is that RECIST 1.1 represents a new layer of complexity and opportunity for error among oncologists and radiologists new to clinical research, since the criteria are not routinely used in daily clinical practice. Only a fraction of physicians are even vaguely familiar with the guidelines, particularly those at nonacademic sites that do not regularly participate in clinical studies. 

For seasoned investigative sites, the bigger issue may be simultaneously juggling the old and new criteria, as a mass migration to RECIST 1.1 is at best several years away. There are still multiple trials ongoing with the old RECIST, and sponsors are opting to use the original criteria for some of their upcoming studies—especially if they're planning trials for an investigational compound that will be compared to a marketed product that was investigated using RECIST 1.0. There are also practical challenges that RECIST 1.1 present for sites, such as differential cataloging and reporting of nodal versus non-nodal target lesions. 

Measuring lymph nodes in conformance with the new criteria will be particularly demanding, if only because the methodology is new and entirely untried. While it may be useful for radiologists to have oncology analysis software with automated lesion measurements and volumetric calculations,

  the reality is that most sites still do all their measurements manually. 

As with any criterion involving tumor measurements, the key to accurate and reproducible assessment of response to treatment in clinical practice and clinical trials is the involvement of a radiologist experienced in cancer imaging. The assessment of response not only requires precise tumor size measurements but also in-depth understanding of the complications of cancer therapies and a knowledge of the disease-specific patterns of tumor worsening. 

Given the measurement complexities that arise with RECIST 1.1, site training and coaching are even more crucial today. Since optimal results from RECIST assessments are dependent on radiologists as well as oncologists, ideally both parties should attend investigator meetings for formal training. Web conferencing, teleconferencing, and prerecorded DVDs are also readily available for site-based RECIST training. The Web site 

 which is devoted to RECIST and hosted by Perceptive Informatics, is a self-education tool that includes real-life examples of how to apply the new rules. 

Sponsors planning studies using central imaging should talk with their imaging vendor before finalizing protocols and, if RECIST 1.1 is under consideration, decide how to accurately train physicians to use the criteria. Some of its features, such as assessment of progression and lymph nodes, may be particularly important for specific trials and indications. On the other hand, for Phase I and II trials, sponsors might want to try out the advantages of RECIST 1.1 and perhaps pursue regulatory endorsement. 

Switching to RECIST 1.1 is generally not advised if comparison to historical data or previous trials of the same compound or other indications is planned. The breast cancer treatment Herceptin has been studied extensively utilizing the original RECIST, making an apples-to-apples comparison impossible against any other therapy trying to prove its noninferiority based on RECIST 1.1 assessment guidelines, especially considering the measurement of frequently present lytic bone lesions as target lesions in this patient population, which was not an option previously. 

The new criteria are also difficult to implement for treatments aimed at mesothelioma, which grows haphazardly, or prostate cancer, which grows slowly once it metastasizes to the skeletal system. Trials of therapies for gastrointestinal stromal tumors (GIST), in which the tumor may never fully disappear, would also be poor RECIST candidates. So would experimental treatments for hepatocellular carcinoma, due to the relative complexity of viable tumor tissue versus necrotic tissue available for evaluation. For studies of these types, sponsors may want to consult with their imaging vendor about making indication-specific modifications to RECIST via medical imaging charters for centralized review. 

Some study sponsors may simply want to wait to see how regulatory agencies respond to submissions utilizing the new RECIST standards. In general, the U.S. Food & Drug Administration looks for a tight fit between the protocol, statistical analysis plan, and the assessment criteria defined in the medical imaging charter. RECIST, with or without adaptations to it, or any other method or self-developed criteria may be acceptable to the agency as long as it makes scientific sense, is reasonably explained and justified, and supports a sponsor's claim of efficacy.  

Consistency is imperative if sponsors hope to get study results approved by regulators, regardless of which set of imaging rules and requirements get adopted. Significant levels of variability in how investigators follow RECIST could effectively erase many of its newfound advantages. 

,* MD, PhD, MBA, is Senior Medical Director, Head of Oncology, email: 

, PhD, is Associate Medical Director, Associate Head of Oncology, both for Perceptive Informatics.

*To whom all correspondence should be addressed.

1. P. Therasse, S.G. Arbuck, E.A. Eisenhauer et al., "New Guidelines to Evaluate the Response to Treatment in Solid Tumors (RECIST Guidelines)," 

2. E.A. Eisenhauer, P. Therasse, J. Bogaerts et al., "New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1)," 

3. J. Verweij, P. Therasse, E. Eisenhauer, "Cancer Clinical Trial Outcomes: Any Progress in Tumour-Size Assessment?" 

4. J.E. Husband, L.H. Schwartz, J. Spencer et al., "Evaluation of the Response to Treatment of Solid Tumours—A Consensus Statement of the International Cancer Imaging Society," 

5. S.H. Kim, S.C. Kim, B.I. Choi, M.C. Han, "Uterine Cervical Carcinoma: Evaluation of Pelvic Lymph Node Metastasis with MR Imaging," 

7. J. Bogaerts, R. Ford, D. Sargent et al., "Individual Patient Data Analysis to Assess Modifications to the RECIST Criteria," European Journal of Cancer 45 (2) 248-60 (2009).     

8. L.H. Schwartz, J. Bogaerts, R. Ford, L. Shankar, P. Therasse, S. Gwyther, E.A. Eisenhauer, "Evaluation of Lymph Nodes with RECIST 1.1," 

Articles

Partnerships in Clinical Trials

The when and why of using the new RECIST 1.1 criteria without abandoning the old.

RECIST in the Real World

The global market in sales for oncology drugs is anticipated to expand from around $48 billion in 2008 to more than $85 billion in 2013. This is based on 2008 data from Cutting Edge Information. Currently, more than 4700 clinical trials are in progress for oncology drugs.    

John W. Hubbard, PhD, FCP, Global President, ICON Clinical Research, had shared in an interview conducted in 2009 that ICON was seeing increased activity in the oncology space and had in fact added three more oncologists to its corporate staff in the United States. Exploring the reasons behind the increase, as well as the apparent, but not wholesale, migration of oncology trials from academia to mainstream trial venues, Hubbard noted the toxicity shift in medicines available for cancer treatment. "The older drugs were very toxic with side effects that needed to be managed," said Hubbard. "With the newer drugs, they are more targeted and the side effects aren't as bad. And there are more of them, so they are moving into a traditional drug development model." 

In fact, in a recent survey from US Oncology, 53% of the respondents felt that recruiting patients to clinical trials for targeted therapies will be less difficult than large-scale randomized trials of more traditional cytotoxic therapies. The survey respondents included a mix of oncologists (67%), and the balance clinical research professionals (33%). 

The US Oncology respondents believed that subject recruitment for clinical trials is most successful at academic medical centers (AMCs), and the reasons given in order were: better patient acceptance, large patient population/database, and more staff. 

Meanwhile, getting trials up and running remains a two-fold problem, one that AMCs may need to heed. The US Oncology survey found that regulatory red tape was the primary cause that slowed down a trial's approval. Couple that with another study from KMR Group on site contracting practices, which found site contract approval time is five to six weeks on average, but double for an oncology trial, with problems specific to start up. KMR Group attributes the lengthened oncology time to both a greater tendency for those studies to be conducted at institutional sites, which tend to take longer, and the greater complexity of oncology protocols, e.g., due to patient issues. 

Phase News

Trials in Oncology Only Going Up

Hstorically, the endpoint gold standard for demonstrating clinical benefit in oncology drug trials has been and still is overall survival (OS). From the FDA perspective, OS provides the most objective and comprehensive means of evaluation, but the analysis is not without its drawbacks. 

Because evaluation of OS requires large patient numbers and much longer follow-up compared with other endpoints, data receipt is delayed. Trials based primarily on survival are therefore always more expensive and time consuming, and FDA approval takes longer than when based on studies using other accepted primary efficacy endpoints, such as time to progression (TTP) or objective response rate (ORR). Plus, overall survival may be confounded by subsequent therapies, unlike endpoints such as TTP or ORR, which are often used as surrogates for OS in patients with solid tumors. 

These tumor assessment endpoints are less expensive and much more time effective than OS, and are, therefore, an attractive alternative for demonstrating efficacy. Because they are based on subjective evaluations (i.e., clinical or radiological observations), however, they are also less objective than overall survival and must be used in accordance with strict quality control measures to ensure validity. 

Specifically, certain design features can be incorporated into a clinical trial to minimize bias and increase precision and accuracy of potentially subjective observer-dependent assessments. To increase uniformity of efficacy endpoints based on tumor assessments, sponsors and CROs must pay special attention to the blinding of patient data. Accordingly, the use of central (external) review committees is recommended, because without independent central review, bias stemming from the sponsor or study monitor's familiarity with particular patients may influence endpoint assessments. Moreover, the FDA can and will question the validity of the conclusions drawn if stringent processes are not put in place to reduce the potential for bias. 

Efforts to encourage uniform interpretation of endpoint data among assessors and to minimize assessment variability across the study should be part of the study design prior to patient enrollment. A good example of a design intended to reduce variability of endpoint assessments is a double-blind read with adjudication. By this process, radiological images are initially assessed by multiple, often two, independent blinded reviewers. If the reviewers disagree, then a third adjudicating assessment (i.e., a tie-breaker) is made by an additional reviewer who may or may not be blinded to prior assessments. To further minimize variability, all independent reviewers should be uniformly trained and periodically tested to evaluate intra- and inter-reader variability. 

Implementation of double-blind read with adjudication in Phase III oncology trials became more widespread in the late '90s based, in large part, on the need for accurate, unbiased radiological assessment in patients with solid tumors. This need arose partly because of the addition of Subpart H to new drug approval regulations promulgated in 1992, which allowed for accelerated drug approval using surrogate endpoints involving radiological assessment of tumor sizing. By the end of the millennium, however, it had become apparent that although endpoints such as ORR can support regulatory approval in select solid tumors, relief of tumor-related symptoms and drug toxicity should also be considered when making approval decisions. 

Moving into the 21st century, solid tumor trials started using independent endpoint assessment committees (EACs) that used the data from the independent imaging assessment committee in conjunction with information from sites. Although these endpoint assessment and adjudication committees use a combination of independent blinded imaging data and site data, their goals and processes are the same as the independent imaging assessment committee, and their determination of response is often positioned as the primary efficacy result of a Phase III trial. 

This is particularly important because tumor response alone is not always sufficient data for regulatory review. The FDA and other regulatory agencies are looking increasingly to a more objective and encompassing view of the drug's effect, and the use of the EAC offers an evaluation of this efficacy. Data for regulatory submission is not only comprised of bias-free tumor assessment with standardized quantification (e.g., WHO or RECIST criteria), but must also include clinical and pathology data to confirm the radiological analysis. 

Not only do EACs reduce physician bias (blinded reviews coupled with off-site specialists serve to eliminate the potential for prior knowledge of the status of the patient) but they also help to overcome the limitations inherent in imaging that may make precise diagnosis difficult. Especially valuable for subjective endpoints, they provide a far more complete method for determining total tumor and drug effect when a complicated definition of efficacy is required. 

Still relatively novel, EACs are most prevalent in oncology trials, although the FDA's push toward more robust and definitive datasets for regulatory approval means that they will become important to all therapeutic areas in the future. 

Current FDA efforts to draft guidance documents for EACs closely resemble those for cancer endpoints in clinical trials, including survival, tumor response, response duration, relief of symptoms, or composite clinical benefit endpoints. The FDA has intended to develop the series of guidances on oncology endpoints through a process that includes public workshops and discussions before its Oncologic Drugs Advisory Committee, and each subsequent guidance is to focus on endpoints for specific cancer types to support drug approval or labeling claims. 

For oncology trials, the EAC is defined by the oncologist(s), who utilizes data beyond radiology images, including clinical data, pathology results, and other physical measurements (e.g., skin lesions for cutaneous lymphoma, etc.) to more holistically determine the disease status of the patient. Specifically, board-certified oncologists are required, but it is also often of value to have radiology and pathology representation on the committee. All members must be trained under an EAC chair to minimize variability among assessments and to determine the different roles each clinical specialist plays in them. 

The EAC chair should be a member of the committee and will be the point of authority for determining information needed for assessment (i.e., adverse events, histology, calibrated photos, magnetic resonance imaging, etc.). They  should work with the imaging CRO, sponsor, FDA, and radiologist to design the EAC charter, which is essential to ensuring unbiased assessment of all clinical outcomes. Specifically, this responsibility includes development of a decision algorithm for response assessment and determination of work load and time estimates for all committee members. Once the charter and training and testing programs have been designed, full training commences and the program is put into operation. 

Objectivity of the earlier mentioned guidances and workshops is especially critical in fields in which endpoints are determined by clinical or radiological examinations, rather than by predefined laboratory measurements. This is where an independent EAC can be invaluable. Through a charter, EACs can facilitate an unbiased assessment of clinical outcomes in a multicenter Phase III oncology trial to enable a uniform, controlled-assessment process that is independent of the sponsor. Most importantly, the endpoint assessment and adjudication committee charter enables objectivity of endpoint assessment and approximates the critical review that the FDA might impose on clinical endpoint data. The endpoint assessment and adjudication committee charter should be reviewed rigorously in consultation with the FDA, resulting in a charter that may prove to be a useful example in generating independent assessment of pivotal clinical outcomes.

For Phase III registration trials, regulatory agencies must be able to reach objective and definitive conclusions from data. Independence and consistency in the interpretation of the clinical endpoints across different geographic areas and over the course of the study is a primary challenge that can be met by using a central assessment and adjudication committee. The successes of central review committees and, by extension, the success of the trials, depend on prospectively defined procedures, which are agreed upon by the FDA. In addition, the FDA prefers that radiological assessments be done by a central review. 

This role is almost exclusively performed by an imaging core laboratory. Imaging core laboratories or central imaging laboratories have historically been focused on managing the collection of consistent, high-quality imaging data and ensuring minimal variability through a central reading committee. Integration of clinical data with radiological data is often required to make an assessment, and thus quality control procedures, similar to those for imaging data, should be implemented. 

Additional important considerations, such as defining a procedure for adjudication between a site physician's assessment and assessments made by a central review committee, may also need to be addressed. These adjudications can be very complicated and must be prospectively defined and agreed upon by the FDA in order for them to have any regulatory value. 

If implemented properly, the use of an imaging CRO or an imaging core lab helps minimize the possibility of sponsor bias in the assessment process. A sound data management and statistical analysis plan developed by both parties at the outset of the trial should be in effect throughout and should be designed to prohibit sponsor access to the data until the final outcome is determined. Only when the assessment portion of the trial has closed is it appropriate for the EAC to share conclusions with the sponsor. This way, physicians who help deliver the subject's day-to-day care do not perform assessment of outcomes, and the application of uniform response criteria across all assessment individuals is feasible. 

The technological approach that a CRO takes can have a critical impact on the successful implementation of an EAC and subsequent speed of potential therapeutic approval. The right approach can help facilitate the coordination of data collection and the integrated assessment process to optimize workflow and ensure data validity. A fully digitized process that removes bias in document data handling is especially important for regulatory submission, and a CRO with an automated data management system in place can streamline all data capture and transmission, while displaying and launching all the relevant data from the electronic case report form (see Figure 1). This usually includes clinical site data, independent radiological assessments, and pathology reports with histology images. For melanoma trials, skin lesion images with annotations and measurement will also be required. 

Portals that are part of a larger, Web-based, auditable technology can provide a central point for all trial activity and allow project managers, EAC members, and on-site clinicians to coordinate the assessment procedure. Particularly important are automated procedures for quality control, such as the ability to determine the need for adjudication on a specific case and to forward the image to an appropriate adjudication reviewer. This way, the adjudication reviewer can be distinct from the primary reviewer and can possess specified qualifications (e.g., certain level of training and/or experience). 

These kinds of specialized capabilities will become increasingly important as clinical data and the accompanying reports go digital. Additionally, the ability to provide a digital audit trail coupled with an interactive database that combines clinical information with images, EAC and adjudication results will be a necessity for FDA submission and approval moving ahead. 

Endpoint assessment and adjudication committees are helping to reformat the landscape of oncology drug development. Understanding how EACs fit into the trial process and their potential for improving the chances for regulatory success will become a priority for all oncology sponsors in the coming years, and so the quality control measures and technology requirements necessary for their effective implementation demand our paramount attention. 

PhD, is Director of Regulatory Affairs and Associate Medical Director at WorldCare Clinical, 7 Bulfinch Place, P.O. Box 8908, Boston, MA 02114.

1. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, May 2007, U.S. DHHS, CDER, CBER, 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf

2. International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles For Clinical Trials E 9, Current Step 4 version, dated 5 February 1998, 

http://www.ich.org/LOB/media/MEDIA485.pdf

http://www.asco.org/ascov2/Research+Resources/Research+Activities/ASCO-FDA+Project+on+Cancer+Drug+Approval+Endpoints

4. R. Pazdur, "Endpoints for Assessing Drug Activity in Clinical Trials," 

5. R.C. Kane et al.,"Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma," 

6. Guidance for Industry: Patient-Reported Outcome Measures, Use in Medical Product Development to Support Labeling Claims, December 2009, U.S. DHHS, CDER, CBER, and CDRH, 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

7. Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims—Final. January 2009. U.S. DHHS, FDA, Center for Food Safety and Applied Nutrition, 

http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodLabelingNutrition/ucm073332.htm

How independent endpoint assessment committees can overcome imaging limitations.

Supplements-05-01-2010

RECIST in the Real World

Trials in Oncology Only Going Up

A Team Approach