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Ann Oncol. 2016 Aug;27(8):1638-43. doi: 10.1093/annonc/mdw223. Epub 2016 May 27.

The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies.

Author information

1
Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, UMC Utrecht Cancer Center, Utrecht.
2
Center for Personalized Cancer Treatment (CPCT) Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam.
3
Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam.
4
Center for Personalized Cancer Treatment (CPCT) Department of Radiotherapy, University Medical Center Utrecht, Utrecht.
5
Department of Biometrics, The Netherlands Cancer Institute, Amsterdam.
6
Center for Personalized Cancer Treatment (CPCT) Department of Pathology, University Medical Center Utrecht, Utrecht.
7
Image Sciences Institute.
8
Department of Radiology and Nuclear Medicine.
9
Department of Surgery, University Medical Center Utrecht, Utrecht.
10
Center for Personalized Cancer Treatment (CPCT) Department of Medical Oncology Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam.
11
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.
12
Center for Personalized Cancer Treatment (CPCT) Department of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam e.voest@nki.nl.

Abstract

BACKGROUND:

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 AND METHODS:

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.

RESULTS:

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].

CONCLUSION:

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.

CLINICALTRIALSGOV IDENTIFIER:

NCT01566279.

KEYWORDS:

RECIST 1.1; clinical trial end point; efficacy; time to progression ratio

PMID:
27234642
DOI:
10.1093/annonc/mdw223
[Indexed for MEDLINE]

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