Saskia Litière1, Gaëlle Isaac1, Elisabeth G E De Vries2, Jan Bogaerts1, Alice Chen3, Janet Dancey4, Robert Ford5, Stephen Gwyther6, Otto Hoekstra7, Erich Huang3, Nancy Lin8, Yan Liu1, Sumithra Mandrekar9, Lawrence H Schwartz10, Lalitha Shankar3, Patrick Therasse11, Lesley Seymour4. 1. 1 European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium. 2. 2 University Groningen, Groningen, the Netherlands. 3. 3 National Cancer Institute, Bethesda, MD. 4. 4 Queen's University, Kingston, Ontario, Canada. 5. 5 Clinical Trials Imaging Consulting, Belle Mead, NJ. 6. 6 East Surrey Hospital, Redhill, United Kingdom. 7. 7 Vrije Universiteit Medical Center, Amsterdam, the Netherlands. 8. 8 Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. 9. 9 Mayo Clinic, Rochester, MN. 10. 10 Columbia University Medical Center and New York Presbyterian Hospital, New York, NY. 11. 11 Institut de Recherche International Servier, Paris, France.
Abstract
PURPOSE: The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA. METHODS: We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease. RESULTS: Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs. CONCLUSION: This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.
PURPOSE: The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA. METHODS: We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease. RESULTS: Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs. CONCLUSION: This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.
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