SPECIAL ARTICLE
`New Guidelines to Evaluate the Response to Treatment
`in Solid Tumors
`
`Patrick Therasse, Susan G. Arbuck, Elizabeth A. Eisenhauer, Jantien Wanders,
`Richard S. Kaplan, Larry Rubinstein, Jaap Verweij, Martine Van Glabbeke, Allan
`T. van Oosterom, Michaele C. Christian, Steve G. Gwyther
`
`Anticancer cytotoxic agents go through a process by which
`their antitumor activity—on the basis of the amount of tu-
`mor shrinkage they could generate—has been investigated.
`In the late 1970s, the International Union Against Cancer
`and the World Health Organization introduced specific cri-
`teria for the codification of tumor response evaluation. In
`1994, several organizations involved in clinical research
`combined forces to tackle the review of these criteria on the
`basis of the experience and knowledge acquired since then.
`After several years of intensive discussions, a new set of
`guidelines is ready that will supersede the former criteria. In
`parallel to this initiative, one of the participating groups
`developed a model by which response rates could be derived
`from unidimensional measurement of tumor lesions instead
`of the usual bidimensional approach. This new concept has
`been largely validated by the Response Evaluation Criteria
`in Solid Tumors Group and integrated into the present
`guidelines. This special article also provides some philo-
`sophic background to clarify the various purposes of re-
`sponse evaluation. It proposes a model by which a combined
`assessment of all existing lesions, characterized by target
`lesions (to be measured) and nontarget lesions, is used to
`extrapolate an overall response to treatment. Methods of
`assessing tumor lesions are better codified, briefly within the
`guidelines and in more detail in Appendix I. All other aspects
`of response evaluation have been discussed, reviewed, and
`amended whenever appropriate. [J Natl Cancer Inst 2000;
`92:205–16]
`
`A. PREAMBLE
`
`Early attempts to define the objective response of a tumor to
`an anticancer agent were made in the early 1960s (1,2). In the
`mid- to late 1970s, the definitions of objective tumor response
`were widely disseminated and adopted when it became apparent
`that a common language would be necessary to report the results
`of cancer treatment in a consistent manner.
`The World Health Organization (WHO) definitions published
`in the 1979 WHO Handbook (3) and by Miller et al. (4) in 1981
`have been the criteria most commonly used by investigators
`around the globe. However, some problems have developed with
`the use of WHO criteria: 1) The methods for integrating into
`response assessments the change in size of measurable and
`“evaluable” lesions as defined by WHO vary among research
`groups, 2) the minimum lesion size and number of lesions to be
`
`Journal of the National Cancer Institute, Vol. 92, No. 3,
`
`recorded also vary, 3) the definitions of progressive disease are
`related to change in a single lesion by some and to a change in
`the overall tumor load (sum of the measurements of all lesions)
`by others, and 4) the arrival of new technologies (computed
`tomography [CT] and magnetic resonance imaging [MRI]) has
`led to some confusion about how to integrate three-dimensional
`measures into response assessment.
`These issues and others have led to a number of different
`modifications or clarifications to the WHO criteria, resulting in
`a situation where response criteria are no longer comparable
`among research organizations—the very circumstance that the
`WHO publication had set out to avoid. This situation led to an
`initiative undertaken by representatives of several research
`groups to review the response definitions in use and to create a
`revision of the WHO criteria that, as far as possible, addressed
`areas of conflict and inconsistency.
`In so doing, a number of principles were identified:
`
`1) Despite the fact that “novel” therapies are being developed
`that may work by mechanisms unlikely to cause tumor re-
`gression, there remains an important need to continue to de-
`scribe objective change in tumor size in solid tumors for the
`foreseeable future. Thus, the four categories of complete re-
`sponse, partial response, stable disease, and progressive dis-
`ease, as originally categorized in the WHO Handbook (3),
`should be retained in any new revision.
`2) Because of the need to retain some ability to compare favor-
`able results of future therapies with those currently available,
`it was agreed that no major discrepancy in the meaning and
`the concept of partial response should exist between the old
`and the new guidelines, although measurement criteria would
`be different.
`3) In some institutions, the technology now exists to determine
`
`Affiliations of authors: P. Therasse, J. Verweij, M. Van Glabbeke, A. T. van
`Oosterom, European Organization for Research and Treatment of Cancer, Brus-
`sels, Belgium; S. G. Arbuck, R. S. Kaplan, L. Rubinstein, M. C. Christian,
`National Cancer Institute, Bethesda, MD; E. A. Eisenhauer, National Cancer
`Institute of Canada Clinical Trials Group, Kingston, ON, Canada; J. Wanders,
`New Drug Development Office Oncology, Amsterdam, The Netherlands; S. G.
`Gwyther, East Surrey Healthcare National Health Service Trust, Redhill, U.K.
`Correspondence to: Patrick Therasse, M.D., European Organization for Re-
`search and Treatment of Cancer Data Center, Avenue Mounier 83/11, 1200
`Brussels, Belgium (e-mail: pth@eortc.be).
`See “Note” following “References.”
`
`© Oxford University Press
`
`
`
`
`JANSSEN EXHIBIT 2046
`Mylan v. Janssen IPR2016-01332
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`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:
`• Measures of antitumor activity, other than tumor shrink-
`age, that may appropriately allow investigation of cyto-
`static agents in phase II trials;
`• Definitions of serum marker response and recommended
`methodology for their validation; and
`• 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:
`
`• 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.
`• 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).
`• 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
`
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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-
`sults 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.
`
`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 ø20 mm
`with conventional techniques or as ø10 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.)
`
`1.3. Response Outcomes in Clinical Trials as a Surrogate for
`Palliative Effect
`
`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.
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`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
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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:
`
`• 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.
`• 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).
`• 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
`lesions
`
`CR
`CR
`PR
`SD
`PD
`Any
`Any
`
`Nontarget lesions
`
`New lesions
`
`CR
`Incomplete response/SD
`Non-PD
`Non-PD
`Any
`PD
`Any
`
`No
`No
`No
`No
`Yes or no
`Yes or no
`Yes
`
`Overall
`response
`
`CR
`PR
`PR
`SD
`PD
`PD
`PD
`
`*CR 4 complete response; PR 4 partial response; SD 4 stable disease; and
`PD 4 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 made.)
`
`3.4. Progression-Free Survival/Time to Progression
`
`This document focuses primarily on the use of objecti