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The Oncologist, Vol. 13, No. suppl_2, 1-3, April 2008; doi:10.1634/theoncologist.13-S2-1
© 2008 AlphaMed Press
SARC-CTOS Imaging Symposium: Introduction to the Problem from a Clinical Perspective
University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA
Key Words. Sarcoma • Imaging • Response • Chemotherapy
Correspondence: Robert Benjamin, M.D., University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 450, Houston, Texas 77030, USA. Telephone: 713-792-3626; Fax: 713-794-1934; e-mail: rbenjami{at}mdanderson.org
Received August 20, 2007; accepted for publication December 10, 2007.
Disclosure: R.B. has acted as a consultant to Novartis. No other potential conflicts of interest were reported by the author, planners, reviewers, or staff managers of this article.
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Failure to correctly design clinical trials precludes effective evaluation of yield data. For instance, the Response Evaluation Criteria in Solid Tumors were developed using unidimensional measurements, while the World Health Organization criteria were based on bidimensional measurements. Attempts to compare data from the two response criteria have been problematic. There is an ongoing debate regarding the definition of what constitutes response, and there is a need to update the existing criteria. Advances in imaging techniques need to be evaluated and added into new response criteria. As sarcoma patients can derive clinical benefit from therapy without sizable tumor shrinkage, identifying other qualitative changes, such as ossification of osteosarcomas, should also be incorporated into new response criteria. This article reviews existing approaches to assess response criteria in sarcomas, and explores the role of modern imaging in the evaluation of clinical benefit.
Recent advances in the imaging and treatment of sarcomas have necessitated the re-evaluation of what constitutes clinical benefit. In November 2004, several radiologists and oncologists convened for a special symposium during the Connective Tissue Oncology Society (CTOS) annual meeting to discuss the use of various imaging modalities in the diagnosis and response assessment of sarcomas. The purpose of this symposium was to explore the role of modern imaging in the evaluation of clinical benefit.
One of the pioneers in defining response criteria, E. J. Freireich, said "responders always live longer than ‘nonresponders,’ unless they die of toxicity" (E.J. Freireich, personal communication). While this may be an intuitively obvious concept, it is actually derived from Dr. Freireich's early work in the 1960s at the National Cancer Institute. At the time, the only therapeutic option for pediatric acute leukemia was single-agent chemotherapy. While children who experienced hematologic improvement survived longer than those who did not, Freireich and his colleagues noted that the difference between the two survival curves was essentially dependent on the amount of time the patients spent in response (Fig. 1) [1]. A more recent study by A. van den Abbeele and coworkers showed that time to treatment failure in patients with gastrointestinal stromal tumors (GISTs) who were treated with imatinib mesylate did not differ between patients who had a >50% response based on bidimensional World Health Organization (WHO) criteria and those who had a <50% response (van den Abbeele, personal communication). Similarly, nonsignificant differences were observed when Response Evaluation Criteria in Solid Tumors (RECIST) were employed for the assessment of the same patient population (Fig. 2)[2]. Thus, in patients with GISTs, survival is often comparable between responders and nonresponders. The conventional paradigm that responders do better, that is, live longer, than nonresponders is therefore not always true, suggesting that if responders do not live longer than nonresponders in a clinical trial, response was not correctly defined.
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The origins of the currently used response criteria begin with those defined by D. A. Karnofsky in 1961 [3]. Karnofsky suggested that response should be a surrogate marker for a meaningful endpoint such as survival or progression, and he proposed that it be objective, quantifiable, and reproducible. He defined two response categories, IA and IB. A category IA response reflected symptomatic improvement and was defined as a distinct subjective benefit with favorable objective changes (percent not specified) in all measurable criteria for
1 month. In contrast, a category IB response reflected a change in tumor size and was defined as an objective regression of 50% for 1 month in a relatively asymptomatic patient. Category IB responses have become more relevant as cancers are being treated more often in the absence of symptoms than was the case soon after the introduction of chemotherapy.
Karnofsky's response criteria have evolved into the currently used modern anatomic tumor response criteria, namely, the WHO criteria and the RECIST [4–6]. The criteria for Karnofsky's category IB response developed into the criteria for a WHO partial response (PR), which is defined as a 50% decrease in the sum of the products of the perpendicular diameters of all measurable disease, as well as the absence of the appearance of any new lesions [4, 7]. However, the WHO criteria were found by many investigators to be sometimes unclear and poorly reproducible. In addition, they became outdated as newer imaging technologies were introduced [6, 8]. The RECIST were developed for the purpose of standardization and simplification. While the WHO criteria are based on bidimensional measurements, the RECIST are calculated using unidimensional measurements, which the RECIST authors consider to be equally informative [5]. Analogous to a Karnofsky category IB response and a WHO PR, the RECIST PR is defined as a 30% decrease in the sum of the single maximum diameters of all measurable disease, as well as the absence of the appearance of any new lesions [5]. The RECIST developers emphasized that no major discrepancies should exist in the meaning and concept of PR between the RECIST and WHO criteria, so past and future results could be compared. Further, the authors stressed that there is always room for improvement: implementation and acceptance of the RECIST are not meant to discourage the development of new tools that may provide more reliable surrogate endpoints [5].
Karnofsky's category IA response may be more appropriate for assessing response in sarcomas, because sarcoma patients can derive clinical benefit from therapy without sizable tumor shrinkage. In the 1970s (i.e., after Karnofsky's work but before publication of the WHO criteria and RECIST), some investigators suggested classifying a 25% reduction in tumor size as a PR. Indeed, the activity of both doxorubicin and high-dose methotrexate in osteosarcoma was identified using 25% regression as an endpoint [9–11]. In 1976, Moertel and Hanley devised an interesting strategy for assessing clinician error rates associated with distinguishing between masses reduced by 25% and 50% via palpation [12]. Those investigators created a model in which 12 solid spheres were embedded in layers of foam rubber up to 1.5 inches thick to approximate an abdominal tumor mass. The investigators asked 16 experienced oncologists at a national meeting to measure the size of these tumors through palpation and declare which ones represented a response to therapy. Unknown to the oncologists, two of these masses were identical, while another two were nearly identical. Moertel and Hanley found that the false-positive rates were 25% when 25% reduction was used as a criterion and 6.8% when 50% reduction was used [12]. The authors concluded that a 50% reduction criterion should therefore be employed in practice, with the expectation of 5%–10% human error. However, with modern imaging, error rates have improved, and smaller changes in tumor size can be more readily and accurately detected.
While investigators still actively debate what constitutes response, they are more likely to agree on the identification of disease progression. The WHO response criteria define progressive disease (PD) as a 25% increase in the sum of the products of perpendicular diameters of all measurable disease as well as the appearance of any new lesions [4, 7]. Thus, if progressive disease exists in any lesion or when a new lesion appears, then the overall results will be classified as "progressive disease." The WHO criteria authors also stated that although the use of a 25% increase in one or more measurable lesions or appearance of a new lesion is recommended for defining progression of disease, this percentage should not necessarily be regarded as influencing the management of the patient; in other words, disease progression is not a criterion for stopping treatment [4, 7]. In contrast to the WHO criteria, the RECIST define PD as a 20% increase in the sum of the single maximum diameters of all measurable disease as well as the appearance of any new lesions [4]. The RECIST PD definition thus requires more progression to occur to fulfill the PD criterion, because it encompasses evaluation of multiple lesions. This definition has been controversial, because relatively small lesions that have doubled in size may not necessarily qualify as PD, while a new, previously undetectable lesion that has doubled in size would qualify. Thus, major discrepancies exist between the WHO and RECIST criteria for PD, and they cannot be readily compared when input into the same database. This situation needs to be resolved, as response criteria are revised and updated.
As mentioned above, response to cancer treatment does not always translate into a noticeable change in tumor size, particularly in sarcomas. Qualitative changes in sarcomas may be negative, such as the ossification of osteosarcomas, or positive, as is observed during the myxoid degeneration in GISTs as well as various fibrotic and/or cystic changes in other sarcomas. Therefore, response criteria that can evaluate these types of changes are urgently needed.
Newer imaging modalities may allow such changes to be included in new response criteria. Functional imaging, including positron emission tomography for metabolic activity and dynamic contrast-enhanced magnetic resonance imaging or computed tomography (CT) for vascular changes, has the potential to yield informative data about whether or not a tumor is responding to therapy; these modalities are discussed by several authors in this issue. In addition, better use of standard contrast-enhanced CT could potentially enhance response assessment in sarcomas. Inaccurate response definitions may explain why prognostic factors for response and survival differ. Ideally, proper definition of response criteria for sarcomas that reflect all of the unique characteristics of these tumors should ultimately result in more effective treatments that translate to maximum clinical benefit for sarcoma patients.
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[Abstract/Free Full Text] - Jaffe CC. Response assessment in clinical trials: Implications for sarcoma clinical trial design. The Oncologist 2008;13(suppl 2):14–18.
[Abstract/Free Full Text] - World Health Organization. Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland: World Health Organization, 1979. Publication No. 48.
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[Abstract/Free Full Text] - Bonadonna G, Monfardini S, De Lena M et al. Phase I and preliminary phase II evaluation of adriamycin (NSC 123127). Cancer Res 1970;30:2572–2582.
[Abstract/Free Full Text] - Jaffe N. Recent advances in the chemotherapy of metastatic osteogenic sarcoma. Cancer 1972;30:1627–1631.[CrossRef][Medline]
- Bonadonna G, Beretta G, Tancini G et al. [Adriamycin as a single agent in various forms of advanced neoplasia of adults and children (author's transl).]. Tumori 1974;60:373–391; Italian.[Medline]
- Moertel CG, Hanley JA. The effect of measuring error on the results of therapeutic trials in advanced cancer. Cancer 1976;38:388–394.[CrossRef][Medline]
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