title: The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies.
abstract: Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio.
  
  
  
  Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined.
  
  
  
  Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorff's α-coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496].
  
  
  
  The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS.
  
  
  
  NCT01566279.
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, UMC Utrecht Cancer Center, Utrecht.
authors.forename: G A
authors.initials: GA
authors.lastname: Cirkel
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam.
authors.forename: F
authors.initials: F
authors.lastname: Weeber
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam.
authors.forename: S
authors.initials: S
authors.lastname: Bins
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Radiotherapy, University Medical Center Utrecht, Utrecht.
authors.forename: C G M
authors.initials: CG
authors.lastname: Gadellaa-van Hooijdonk
authors.affiliation: Department of Biometrics, The Netherlands Cancer Institute, Amsterdam.
authors.forename: E
authors.initials: E
authors.lastname: van Werkhoven
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Pathology, University Medical Center Utrecht, Utrecht.
authors.forename: S M
authors.initials: SM
authors.lastname: Willems
authors.affiliation: Image Sciences Institute.
authors.forename: M
authors.initials: M
authors.lastname: van Stralen
authors.affiliation: Department of Radiology and Nuclear Medicine.
authors.forename: W B
authors.initials: WB
authors.lastname: Veldhuis
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht.
authors.forename: I
authors.initials: I
authors.lastname: Ubink
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam.
authors.forename: N
authors.initials: N
authors.lastname: Steeghs
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam.
authors.forename: M J
authors.initials: MJ
authors.lastname: de Jonge
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, UMC Utrecht Cancer Center, Utrecht.
authors.forename: M H G
authors.initials: MH
authors.lastname: Langenberg
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam Department of Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam.
authors.forename: S
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam.
authors.forename: M P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Center for Personalized Cancer Treatment (CPCT) Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam e.voest@nki.nl.
authors.forename: E E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000706:statistics & numerical data*; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D066066:Response Evaluation Criteria in Solid Tumors; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D000068338:Everolimus
keywords: RECIST 1.1; clinical trial end point; efficacy; time to progression ratio