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`Breast Cancer Vol. 12 Supplement 2005 changes in tumor volume or changes in tumor metabolism that may herald shrinkage. However, these techniques are not yet widely available, and many have not been validated. Fur- thermore, it was recognized that the utility of response cri- teria to date had not been related to precision of measure- ment. The definition of a partial response, in particular, is an arbitrary convention--there is no inherent meaning for an individual patient of a 50% decrease in overall tumor load. It was not thought that increased precision of measurement of tumor volume was an important goal for its own sake. Rather, standardization and simplification of methodology were desirable. Nevertheless, the guidelines proposed in this document are not meant to discourage the development of new tools that may provide more reliable surrogate end points than objective tumor response for predicting a poten- tial therapeutic benefit for cancer patients. 4) Concerns regarding the ease with which a patient may be considered mistakenly to have disease progression by the current WHO criteria (primarily because of measurement er- ror) have already led some groups such as the Southwest Oncology Group to adopt criteria that require a greater in- crease in size of the tumor to consider a patient to have progressive disease (5). These concerns have led to a similar change within these revised WHO criteria (see Appendix II). 5) These criteria have not addressed several other areas of re- cent concern, but it is anticipated that this process will con- tinue and the following will be considered in the future: (cid:12)9 Measures of antitumor activity, other than tumor shrink- age, that may appropriately allow investigation of cyto- static agents in phase II trials; (cid:12)9 Definitions of serum marker response and recommended methodology for their validation; and (cid:12)9 Specific tumors or anatomic sites presenting unique com- plexities. B. BACKGROUND These guidelines are the result of a large, international col- laboration. In 1994, the European Organization for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) of the United States, and the National Cancer Institute of Canada Clinical Trials Group set up a task force (see Appendix III) with the main objective of reviewing the existing sets of criteria used to evaluate response to treatment in solid tumors. After 3 years of regular meetings and exchange of ideas within the task force, a draft revised version of the WHO criteria was produced and widely circulated (see Appendix IV). Comments received (response rate, 95%) were compiled and discussed within the task force before a second version of the document integrating relevant comments was issued. This second version of the document was again circulated to external reviewers who were also invited to participate in a consensus meeting (on be- half of the organization that they represented) to discuss and finalize unresolved problems (October 1998). The list of partici- pants to this consensus meeting is shown in Appendix IV and included representatives from academia, industry, and regula- tory authorities. Following the recommendations discussed dur- ing the consensus meeting, a third version of the document was produced, presented publicly to the scientific community (American Society for Clinical Oncology, 1999), and submitted to the Journal of the National Cancer Institute in June 1999 for official publication. Data from collaborative studies, including more than 4000 patients assessed for tumor response, support the simplification of response evaluation through the use of unidimensional mea- surements and the sum of the longest diameters instead of the conventional method using two measurements and the sum of the products. The results of the different retrospective analyses (comparing both approaches) performed by use of these differ- ent databases are described in Appendix V. This new approach, which has been implemented in the following guidelines, is based on the model proposed by James et al. (6). C. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) GUIDELINES 1. Introduction The introduction explores the definitions, assumptions, and purposes of tumor response criteria. Below, guidelines that are offered may lead to more uniform reporting of outcomes of clinical trials. Note that, although single investigational agents are discussed, the principles are the same for drug combinations, noninvestigational agents, or approaches that do not involve drugs. Tumor response associated with the administration of anti- cancer agents can be evaluated for at least three important pur- poses that are conceptually distinct: (cid:12)9 Tumor response as a prospective end point in early clinical trials. In this situation, objective tumor response is employed to determine whether the agent/regimen demonstrates suffi- ciently encouraging results to warrant further testing. These trials are typically phase II trials of investigational agents/ regimens (see section 1.2), and it is for use in this precise context that these guidelines have been developed. (cid:12)9 Tumor response as a prospective end point in more definitive clinical trials designed to provide an estimate of benefit for a specific cohort of patients. These trials are often randomized comparative trials or single-arm comparisons of combinations of agents with historical control subjects. In this setting, ob- jective tumor response is used as a surrogate end point for other measures of clinical benefit, including time to event (death or disease progression) and symptom control (see sec- tion 1.3). (cid:12)9 Tumor response as a guide for the clinician and patient or study subject in decisions about continuation of current therapy. This purpose is applicable both to clinical trials and to routine practice (see section 1.1), but use in the context of decisions regarding continuation of therapy is not the primary focus of this document. However, in day-to-day usage, the distinction among these uses of the term "tumor response" can easily be missed, unless an effort is made to be explicit. When these differences are ignored, inappropriate methodology may be used and incorrect conclusions may result. 1.1. Response Outcomes in Daily Clinical Practice of Oncology The evaluation of tumor response in the daily clinical practice of oncology may not be performed according to predefined cri- teria. It may, rather, be based on a subjective medical judgment that results from clinical and laboratory data that are used to assess the treatment benefit for the patient. The defined criteria 206 SPECIAL ARTICLE Journal of the National Cancer Institute, Vol. 92, No. 3, February 2, 2000 ~q17
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`developed further in this document are not necessarily appli- cable or complete in such a context. It might be appropriate to make a distinction between "clinical improvement" and "objec- tive tumor response" in routine patient management outside the context of a clinical trial. 1.2. Response Outcomes in Uncontrolled Trials as a Guide to Further Testing of a New Therapy "Observed response rate" is often employed in single-arm studies as a "screen" for new anticancer agents that warrant further testing. Related outcomes, such as response duration or proportion of patients with complete responses, are sometimes employed in a similar fashion. The utilization of a response rate in this way is not encumbered by an implied assumption about the therapeutic benefit of such responses but rather implies some degree of biologic antitumor activity of the investigated agent. For certain types of agents (i.e., cytotoxic drugs and hor- mones), experience has demonstrated that objective antitumor responses observed at a rate higher than would have been ex- pected to occur spontaneously can be useful in selecting anti- cancer agents for further study. Some agents selected in this way have eventually proven to be clinically useful. Furthermore, cri- teria for "screening" new agents in this way can be modified by accumulated experience and eventually validated in terms of the efficiency by which agents so screened are shown to be of clini- cal value by later, more definitive, trials. In most circumstances, however, a new agent achieving a response rate determined a priori to be sufficiently interesting to warrant further testing may not prove to be an effective treat- ment for the studied disease in subsequent randomized phase III trials. Random variables and selection biases, both known and unknown, can have an overwhelming effect in small, uncon- trolled trials. These trials are an efficient and economic step for initial evaluation of the activity of a new agent or combination in a given disease setting. However, many such trials are per- formed, and the proportion that will provide false-positive re- suits is necessarily substantial. In many circumstances, it would be appropriate to perform a second small confirmatory trial be- fore initiating large resource-intensive phase III trials. Sometimes, several new therapeutic approaches are studied in a randomized phase II trial. The purpose of randomization in this setting, as in phase III studies, is to minimize the impact of random imbalances in prognostic variables. However, random- ized phase II studies are, by definition, not intended to provide an adequately powered comparison between arms (regimens). Rather, the goal is simply to identify one or more arms for further testing, and the sample size is chosen so to provide reasonable confidence that a truly inferior arm is not likely to be selected. Therefore, reporting the results of such randomized phase II trials should not imply statistical comparisons between treatment arms. 1.3. Response Outcomes in Clinical Trials as a Surrogate for Palliative Effect determined statistical analysis plan provides for matching of relevant prognostic variables between case subjects and a de- fined series of control subjects. Otherwise, there must be, at the very least, prospectively determined statistical criteria that pro- vide a very strong justification for assumptions about the re- sponse rate that would have been expected in the appropriate "control" population (untreated or treated with conventional therapy, as fits the clinical setting). However, even under these circumstances, a high rate of observed objective response does not constitute proof or confirmation of clinical therapeutic ben- efit. Because of unavoidable and nonquantifiable biases inherent in nonrandomized trials, proof of benefit still requires eventual confirmation in a prospectively randomized, controlled trial of adequate size. The appropriate end points of therapeutic benefit for such a trial are survival, progression-free survival, or symp- tom control (including quality of life). 1.3.2. Use in randomized trials. Even in the context of pro- spectively randomized phase III comparative trials, "observed response rate" should not be the sole, or major, end point. The trial should be large enough that differences in response rate can be validated by association with more definitive end points re- flecting therapeutic benefit, such as survival, progression-free survival, reduction in symptoms, or improvement (or mainte- nance) of quality of life. 2. Measurability of Tumor Lesions at Baseline 2.1. Definitions At baseline, tumor lesions will be categorized as follows: measurable (lesions that can be accurately measured in at least one dimension [longest diameter to be recorded[ as ~>20 mm with conventional techniques or as/> 10 mm with spiral CT scan [see section 2.2]) or nonmeasurable (all other lesions, including small lesions [longest diameter <20 mm with conventional tech- niques or < 10 mm with spiral CT scan] and truly nonmeasurable lesions). The term "evaluable" in reference to measurability is not recommended and will not be used because it does not provide additional meaning or accuracy. All measurements should be recorded in metric notation by use of a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of treatment. Lesions considered to be truly nonmeasurable include the following: bone lesions, leptomeningeal disease, ascites, pleural/ pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques, and cystic lesions. (Note: Tumor lesions that are situated in a previously irradi- ated area might or might not be considered measurable, and the conditions under which such lesions should be considered must be defined in the protocol when appropriate.) 2.2. Specifications by Methods of Measurements 1.3.1. Use in nonrandomized clinical trials. The only cir- cumstance in which objective responses in a nonrandomized trial can permit a tentative assumption of a palliative effect (i.e., beyond a purely clinical measure of benefit) is when there is an actual or implied comparison with historical series of similar patients. This assumption is strongest when the prospectively The same method of assessment and the same technique should be used to characterize each identified and reported le- sion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment. Journal of the National Cancer Institute, Vol. 92, No. 3, February 2, 2000 SPECIAL ARTICLE 207 S 18
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`Breast Cancer Vol. 12 Supplement 2005 2.2.1. Clinical examination. Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, documentation by color photography--including a ruler to estimate the size of the lesion--is recommended. 2.2.2. Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and sur- rounded by aerated lung. However, CT is preferable. More de- tails concerning the use of this method of assessment for objec- tive tumor response evaluation are provided in Appendix I. 2.2.3. CT and MRI. CT and MRI are the best currently available and most reproducible methods for measuring target lesions selected for response assessment. Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less in slice thickness. Spiral CT should be performed by use of a 5-mm contiguous reconstruction algorithm; this specification applies to the tumors of the chest, abdomen, and pelvis, while head and neck tumors and those of the extremities usually re- quire specific protocols. More details concerning the use of these methods of assessment for objective tumor response evaluation are provided in Appendix I. 2.2.4. Ultrasound. When the primary end point of the study is objective response evaluation, ultrasound should not be used to measure tumor lesions that are clinically not easily accessible. It may be used as a possible alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. Ultrasound might also be useful to confirm the complete disappearance of superficial lesions usually assessed by clinical examination. Justifications for not using ultrasound to measure tumor lesions for objective response evaluation are pro- vided in Appendix I. 2.2.5. Endoscopy and laparoscopy. The utilization of these techniques for objective tumor evaluation has not yet been fully or widely validated. Their uses in this specific context require sophisticated equipment and a high level of expertise that may be available only in some centers. Therefore, utilization of such techniques for objective tumor response should be restricted to validation purposes in specialized centers. However, such tech- niques can be useful in confirming complete histopathologic response when biopsy specimens are obtained. 2.2.6. Tumor markers. Tumor markers alone cannot be used to assess response. However, if markers are initially above the upper normal limit, they must return to normal levels for a patient to be considered in complete clinical response when all tumor lesions have disappeared. Specific additional criteria for standardized usage of prostate-specific antigen and CA (cancer antigen) 125 response in support of clinical trials are being vali- dated. 2.2.7. Cytology and histology. Cytologic and histologic techniques can be used to differentiate between partial response and complete response in rare cases (e.g., after treatment to differentiate between residual benign lesions and residual ma- lignant lesions in tumor types such as germ cell tumors). Cyto- logic confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required when the mea- surable tumor has met criteria for response or stable disease. Under such circumstances, the cytologic examination of the fluid collected will permit differentiation between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease (if the neoplastic origin of the fluid is confirmed). New techniques to better establish objective tumor response will be integrated into these criteria when they are fully validated to be used in the context of tumor response evaluation. 3. Tumor Response Evaluation 3.1. Baseline Evaluation 3.1.1. Assessment of overall tumor burden and measur- able disease. To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subse- quent measurements will be compared. Only patients with mea- surable disease at baseline should be included in protocols where objective tumor response is the primary end point. Measurable disease is defined by the presence of at least one measurable lesion (as defined in section 2.1). If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 3.1.2. Baseline documentation of "target" and "nontar- get" lesions. All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions and re- corded and measured at baseline. Target lesions should be se- lected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest di- ameter for all target lesions will be calculated and reported as the baseline sum longest diameter. The baseline sum longest diam- eter will be used as the reference by which to characterize the objective tumor response. All other lesions (or sites of disease) should be identified as nontarget lesions and should also be recorded at baseline. Mea- surements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up. 3.2. Response Criteria 3.2.1. Evaluation of target lesions. This section provides the definitions of the criteria used to determine objective tumor response for target lesions. The criteria have been adapted from the original WHO Handbook (3), taking into account the mea- surement of the longest diameter only for all target lesions: complete response--the disappearance of all target lesions; par- tial response--at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; progressive disease--at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions; stable disease--neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive dis- ease, taking as reference the smallest sum longest diameter since the treatment started. 3.2.2. Evaluation of nontarget lesions. This section provides the definitions of the criteria used to determine the objective tumor response for nontarget lesions: complete response--the disappearance of all nontarget lesions and normalization of tu- mor marker level; incomplete response/stable disease--the per- sistence of one or more nontarget lesion(s) and/or the mainte- nance of tumor marker level above the normal limits; and progressive disease--the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions (1). (Note: Although a clear progression of "nontarget" lesions only is exceptional, in such circumstances, the opinion of the 208 SPECIAL ARTICLE Journal of the National Cancer Institute, Vol. 92, No. 3, February 2, 2000 S 19
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`treating physician should prevail and the progression status should be confirmed later by the review panel [or study chair]). 3.2.3. Evaluation of best overall response. The best overall response is the best response recorded from the start of treatment until disease progression/recurrence (taking as reference for pro- gressive disease the smallest measurements recorded since the treatment started). In general, the patient's best response assign- ment will depend on the achievement of both measurement and confirmation criteria (see section 3.3.1). Table 1 provides overall responses for all possible combinations of tumor responses in target and nontarget lesions with or without the appearance of new lesions. (Notes: (cid:12)9 Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of dis- ease progression at that time should be classified as having "symptomatic deterioration." Every effort should be made to document the objective disease progression, even after discon- tinuation of treatment. (cid:12)9 Conditions that may define early progression, early death, and inevaluability are study specific and should be clearly defined in each protocol (depending on treatment duration and treat- ment periodicity). (cid:12)9 In some circumstances, it may be difficult to distinguish re- sidual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recom- mended that the residual lesion be investigated (fine-needle aspiration/biopsy) before confirming the complete response status.) 3.2.4. Frequency of tumor re-evaluation. Frequency of tu- mor re-evaluation while on treatment should be protocol specific and adapted to the type and schedule of treatment. However, in the context of phase II studies where the beneficial effect of therapy is not known, follow-up of every other cycle (i.e., 6-8 weeks) seems a reasonable norm. Smaller or greater time inter- vals than these could be justified in specific regimens or cir- cumstances. After the end of the treatment, the need for repetitive tumor evaluations depends on whether the phase II trial has, as a goal, the response rate or the time to an event (disease progression/ death). If time to an event is the main end point of the study, then routine re-evaluation is warranted of those patients who went off the study for reasons other than the expected event at frequencies to be determined by the protocol. Intervals between evaluations twice as long as on study are often used, but no strict rule can be made. Table 1. Overall responses for all possible combinations of tumor responses in target and nontarget lesions with or without the appearance of new lesions* Target Overall lesions Nontarget lesions New lesions response CR CR No CR CR Incomplete response/SD No PR PR Non-PD No PR SD Non-PD No SD PD Any Yes or no PD Any PD Yes or no PD Any Any Yes PD *CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease. See text for more details. 3.3. Confirmatory Measurement~Duration of Response 3.3.1. Confirmation. The main goal of confirmation of ob- jective response in clinical trials is to avoid overestimating the response rate observed. This aspect of response evaluation is particularly important in nonrandomized trials where response is the primary end point. In this setting, to be assigned a status of partial response or complete response, changes in tumor mea- surements must be confirmed by repeat assessments that should be performed no less than 4 weeks after the criteria for response are first met. Longer intervals as determined by the study pro- tocol may also be appropriate. In the case of stable disease, measurements must have met the stable disease criteria at least once after study entry at a mini- mum interval (in general, not less than 6-8 weeks) that is de- fined in the study protocol (see section 3.3.3). (Note: Repeat studies to confirm changes in tumor size may not always be feasible or may not be part of the standard practice in protocols where progression-free survival and overall survival are the key end points. In such cases, patients will not have "confirmed response." This distinction should be made clear when reporting the outcome of such studies.) 3.3.2. Duration of overall response. The duration of overall response is measured from the time that measurement criteria are met for complete response or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented (taking as reference for pro- gressive disease the smallest measurements recorded since the treatment started). The duration of overall complete response is measured from the time measurement criteria are first met for complete response until the first date that recurrent disease is objectively documented. 3.3.3. Duration of stable disease. Stable disease is measured from the start of the treatment until the criteria for disease pro- gression is met (taking as reference the smallest measurements recorded since the treatment started). The clinical relevance of the duration of stable disease varies for different tumor types and grades. Therefore, it is highly recommended that the protocol specify the minimal time interval required between two mea- surements for determination of stable disease. This time interval should take into account the expected clinical benefit that such a status may bring to the population under study. (Note: The duration of response or stable disease as well as the progression-free survival are influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define a standard follow-up frequency that should take into account many parameters, including disease types and stages, treatment periodicity, and standard practice. However, these limitations to the precision of the measured end point should be taken into account if comparisons among trials are to be mad