Criteria for progression remain loosely based on those outlined in the original WHO guidelines published in the year 1981 (2
). This landmark set of guidelines also included recommendations on performance status reporting and toxicity grading, although the recommendations were mostly based on a consensus agreement instead of data. The WHO criterion for partial response (a 50% decrease in the bidimensional measurement) was derived from an earlier study that quantified the variability of manual tumor measurement (14
). In contrast, the definition of progressive disease (a 25% increase in the size of one or more measurable lesions or the appearance of new lesions) was an educated guess and not based on any specific published data.
The Southwest Oncology Group (SWOG) later proposed a larger criterion for progression (a 50% increase in the sum of tumor measurements) because of concern about the poor reproducibility of the WHO criterion for progression (15
). In the year 2000, the Response Evaluation Criteria in Solid Tumors (RECIST) group (17
) then established the current criterion for progression—a 20% increase in unidimensional measurement or appearance of new lesions. Mathematically, the RECIST criterion is equivalent to a 73% increase in the volume of a spherical tumor mass (), which is somewhat less than the SWOG criterion (a 84% increase in volume) and greater than the WHO criterion (a 40% increase in volume) (18
). The waxing and waning criteria for progression over the past decades contrasts with the criteria for response, which have consistently represented a 65% decrease in volume of a spherical tumor mass despite changes in the measurement technique.
The evolution of criteria for determining response and progression in solid tumor oncology
Reviewing the evolution of response and progression criteria since the landmark publication by Zubrod et al. (1
) in the year 1960, it is striking how the “confirmed response rate” has remained a consistent trial endpoint while the time-to-event endpoints have changed (). The date of disease progression was originally used in clinical trials to calculate the “duration of response” (2
). Of note, a critical analysis of trial endpoints from 61 published reports published in the year 1985 included no mention of TTP or PFS (19
). The SWOG guidelines were the first to formally define PFS: SWOG preferred PFS to duration of response because it can be quantified in all patients rather than just in responders (15
). Despite this precedent, even the latest version of RECIST is intended to “[focus] primarily on the use of objective response endpoints.” Whereas RECIST formally defines duration of response, the guidelines discuss PFS only briefly (17
). In other words, PFS is a recent and sparsely defined endpoint in oncology, whose value as a surrogate for overall survival may not have been the primary consideration when the current progression criteria were developed.
Although progression-based endpoints play an increasingly important role in clinical trial analysis and regulatory drug approval, their value in clinical practice is uncertain. The published criteria for objective progression were developed to guide clinical trial analyses and are not intended to influence the care of individual patients. The WHO guidelines state that a finding of 25% tumor growth “should not necessarily be regarded as influencing the management of the patient” (2
). RECIST similarly states that “it is not intended these RECIST guidelines play a role in [clinical] decision making, except if determined appropriate by the treating oncologist” (20
). In clinical practice, decisions about changing therapy must weigh a number of factors, including tumor burden, cancer-related symptoms, and drug toxicity. This uncertain value of RECIST progression in clinical practice contributes to the debated validity of progression as a trial endpoint, and may result in trial results that are not easily translatable into clinical practice. We propose that objective progression criteria that are developed to be clearly indicative of treatment failure and are closely associated with poorer survival would be the most valuable foundation for clinical trial endpoints. Furthermore, the development of such criteria could also have an important impact on the treatment of individual cancer patients.