Original Research| Volume 109, P196-203, March 2019

Directional inconsistency between Response Evaluation Criteria in Solid Tumors (RECIST) time to progression and response speed and depth

Published:February 07, 2019DOI:


      • A Response Evaluation Criteria in Solid Tumors (RECIST) time to progression (TTP) criterion is tumour size exceeding 120% of its minimum.
      • A simple mathematical model well describes tumour response and relapse in treated patients.
      • Increasing tumour shrinkage rate in this model often leads to paradoxically shorter TTP.
      • This effect is large and frequent enough to invert population-level TTP-based outcomes.
      • We propose an alternative time to event metric that is consistent with shrinkage rate.



      We seek to characterize how faster tumour shrinkage rate (k) can lead to paradoxically shorter Response Evaluation Criteria in Solid Tumors (RECIST) time to progression (‘TTP20’ – tumour size exceeding its minimum by 5 mm and 20%) [1] and, therefore, progression-free survival (PFS). Specifically, we investigate under what conditions this paradoxical behaviour occurs, what fraction of patients satisfy these conditions, whether this phenomenon can invert population-level PFS hazard ratio, and consistency of an alternative time-to-event benefit metric with k.


      We use a mathematical model treating tumour burden as decreasing drug-sensitive and increasing drug-resistant cell subpopulations. We fit this model to data from several clinical trials with different indications [2]. We simulated a more effective treatment and recorded whether patients' TTP20 increased or decreased. We performed a study-level analysis to compare the relationship of speed and depth of response with TTP20 for both the administered ‘control’ and simulated ‘more effective’ drug. We propose and test an alternative benefit metric: the model-projected time that tumour size reaches 120% of baseline (TTB120).


      Depending on indication, 3–27% of patients are estimated to have a paradoxically inverse relationship between k and TTP20. Simulated head-to-head studies show that TTP20-based PFS can favour the less effective drug. In contrast, TTB120 always favours the more effective drug.


      We demonstrate the paradoxical behaviour of RECIST TTP20 – as an exemplar of percent-change-from-nadir based cancer progression criterion – both in theory and in observed patient data at the individual and trial level. We propose an alternative tumour size–based criterion (TTB120) that is directionally consistent with tumour shrinkage rate.

      Graphical abstract


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        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009 Jan; 45: 228-247
      1. Project data sphere.
        . 2018;
        • Therasse P.
        • Arbuck S.G.
        • Eisenhauer E.A.
        • Wanders J.
        • Kaplan R.S.
        • Rubenstein L.
        • et al.
        New guidelines to evaluate the response to treatment in solid tumors. European organization of research and treatment of cancer, national cancer institute of the United States, national cancer institute of Canada.
        J Natl Cancer Inst. 2000 February 2; 92: 205-216
        • Schwartz L.H.
        • Litiere S.
        • de Vries E.
        • Ford R.
        • Gwyther S.
        • Mandrekar S.
        • et al.
        RECIST 1.1-Update and clarification: from the RECIST committee.
        Eur J Cancer. 2016 July; 62: 132-137
        • Lencioni R.
        • Llovet J.M.
        Modified RECIST (mRECIST) assessments for hepatocellular carcinoma.
        Semin Liver Dis. 2010; 30: 52-60
        • Younes A.
        • Hilden P.
        • Coiffier B.
        • Hagenbeek A.
        • Salles G.
        • Wilson W.
        • et al.
        International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017).
        Ann Oncol. 2017 April; 28: 1436-1447
        • Seymour L.
        • Bogaerts J.
        • Perrone A.
        • Ford R.
        • Schwartz L.H.
        • Mandrekar S.
        • et al.
        iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.
        Lancet Oncol. 2017 Mar; 18: e143-e152
        • Yang D.
        • Woodard G.
        • Zhou C.
        • Wang X.
        • Liu Z.
        • Ye Z.
        • et al.
        Significance of different response evaluation criteria in predicting progression-free survival of lung cancer with certain imaging characteristics.
        Thoracic Cancer. 2016 Sep; 7: 535-542
        • Nishino M.
        • Hatabu H.
        • Johnson B.E.
        • McLoud T.C.
        State of the ART: response assessment in lung cancer in the era of genomic medicine.
        Radiology. 2014 April; 271: 6-27
        • Li C.H.
        • Bies R.R.
        • Wang Y.
        • Sharma M.R.
        • Karovic S.
        • Werk L.
        • et al.
        Comparative effects of CT imaging measurement on RECIST end points and tumor growth kinetics modeling.
        Clin Transl Sci. 2016; 9: 43-50
        • Gruenwald V.
        • Dietrich M.
        • Pond G.R.
        Early tumor shrinkage is independently associated with improved overall survival among patients with metastatic renal cell carcinoma: a validation study using the COMPARZ cohort.
        World J Urol. 2018 Sep; 36: 1423-1439
        • Claret L.
        • Jin J.Y.
        • Ferte C.
        • Winter H.
        • Girish S.
        • Stroh M.
        • et al.
        A model of overall survival predicts treatment outcomes with atezolizumab vs chemotherapy in non-small lung cancer based on early tumor kinetics.
        Clin Canc Res. 2018 April;
        • Wolchok J.D.
        • Hoos A.
        • O'Day S.
        • Weber J.S.
        • Hamid O.
        • Lebbe C.
        • et al.
        Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.
        Clin Canc Res. 2009 Nov; 15: 7412-7420
        • Bohnsack O.
        • Hoos A.
        • Ludajic K.
        Adaptation of the immune related response criteria: irRECIST.
        Ann Oncol. 2014 Sept; 25: iv369
        • Byrne M.J.
        • Nowak A.K.
        Modified RECIST criteria for assessment of response in malignant pleural mesothelioma.
        Ann Oncol. 2004 Feb; 15: 257-260
        • Lin N.U.
        • Lee E.Q.
        • Aoyama H.
        • Barani I.J.
        • Barboriak D.P.
        • Baumert B.G.
        • et al.
        Response assessment criteria for brain metastases: proposal from the RANO group.
        Lancet Oncol. 2015 Jun; 16: e270-e278
        • Scher H.I.
        • Halabi S.
        • Tannock I.
        • Morris M.
        • Sternberg C.N.
        • Carducci M.A.
        • et al.
        Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
        J Clin Oncol. 2008 March 1; 26: 1148-1159
        • Scher H.I.
        • Morris M.J.
        • Stadler W.M.
        • Higano C.
        • Basch E.
        • Fizazi K.
        • et al.
        Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3.
        J Clin Oncol. 2016 Apr; 34: 1402-1418
        • Cheson B.D.
        • Pfistner B.
        • Juweid M.E.
        • Gascoyne R.D.
        • Specht L.
        • Horning S.J.
        • et al.
        Revised response criteria for malignant lymphoma.
        J Clin Oncol. 2007 Feb; 25: 579-586
        • Cheson B.D.
        • Fisher R.I.
        • Barrington S.F.
        • Cavalli F.
        • Schwartz L.H.
        • Zucca E.
        • et al.
        Recommendations for initial evaluation, staging, and response assessment of hodgkin and non-hodgkin lymphoma: the lugano classification.
        J Clin Oncol. 2014 Aug; 32: 3059-3068
        • Cheson B.D.
        • Ansell S.
        • Schwartz L.
        • Gordon L.I.
        • Advani R.
        • Jacene H.A.
        • et al.
        Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy.
        Blood. 2016 Nov; 128: 2489-2496
        • Hallek M.
        • Cheson B.D.
        • Catovsky D.
        • Caligaris-Cappio F.
        • Dighiero G.
        • Dohner H.
        • et al.
        Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the national cancer institute–working group 1996 guidelines.
        Blood. 2008 Jan; 111: 5446-5545
        • Hallek M.
        • Cheson B.D.
        • Catovsky D.
        • Caligaris-Cappio F.
        • Dighiero G.
        • Dohner H.
        • et al.
        iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.
        Blood. 2018 Jun; 131: 2745-2760
        • Chatterjee M.S.
        • Elassaiss-Schaap J.
        • Lindauer A.
        • Turner D.C.
        • Sostelly A.
        • Freshwater T.
        • et al.
        Population pharmacokinetic/pharmacodynamic modeling of tumor size dynamics in pembrolizumab-treated advanced melanoma.
        CPT Pharmacometrics Syst Pharmacol. 2017; 6: 29-39
        • Hokanson J.A.
        • Brown B.W.
        • Thompson J.R.
        • Drewinko B.
        • Alexanian R.
        Tumor growth patterns in multiple myeloma.
        Cancer. 1977 March; 39: 1077-1084
        • Williams K.
        • Niu H.
        • Chakravarty A.
        • Jung J.
        • Bargfrede M.
        • Venkatakrishnan D.
        • et al.
        Precision medicine by modeling pharmacokinetic and biomarker drivers of tumor kinetics: assessing effects of alsertib exposure and target SNP status on antitumor activity.
        CPT Pharmacometrics Syst Pharmacol. 2017 February; 101: S5-S99
        • Konishi S.
        • Kitagawa G.
        Information criteria and statistical modeling.
        Biometrics. 2008 Jun; 64: 651-662
        • Park D.I.
        • Kim S.Y.
        • Kim J.O.
        • Jung S.S.
        • Park H.S.
        • Moon J.Y.
        • et al.
        The Prognostic value of the tumor shrinkage rate for progression-free survival in patients with non-small cell lung cancer receiving gefitinib.
        Tuberc Respir Dis. 2015 Oct; 78: 315-320
        • He X.
        • Zhang Y.
        • Ma Y.
        • Zhou T.
        • Zhang J.
        • Hong S.
        • et al.
        Optimal tumor shrinkage predicts long-term outcome in advanced nonsmall cell lung cancer (NSCLC) treated with target therapy.
        Medicine (Baltim). 2016 June; 95: e4176
        • Carbone D.P.
        • Reck M.
        • Paz-Ares L.
        • Creelan B.
        • Horn L.
        • Steins M.
        • et al.
        First-line nivolumab in stage IV or recurrent non-small cell lung cancer.
        N Engl J Med. 2017 June; 376: 2415-2426
        • Stein W.D.
        • Gulley J.L.
        • Schlom J.
        • Madan R.A.
        • Dahut W.
        • Figg W.D.
        • et al.
        Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy.
        Clin Canc Res. 2011 Feb; 17: 907-917