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The AAPS Journal

, 20:72 | Cite as

A Prediction Model of Tumor Progression and Survival in HER2-Positive Metastatic Gastric Cancer Patients Treated with Trastuzumab and Chemotherapy

  • Dongwoo Chae
  • Chung Mo Nam
  • Joo Hoon Kim
  • Choong-Kun Lee
  • Seung-Seob Kim
  • Hyo Song Kim
  • Minkyu Jung
  • Jae Ho Cheong
  • Hyun Cheol Chung
  • Sun Young Rha
  • Kyungsoo Park
Research Article

Abstract

The effects of different patient factors and dose levels of chemotherapeutic agents on clinical outcomes in advanced gastric cancer are not as yet fully characterized. We aimed at developing an integrative model that incorporates dose and covariate information to predict tumor growth and patient survival in advanced gastric cancer patients treated with trastuzumab (T), 5-FU(F)/capecitabine (X) (F or X), and cisplatin (P). Sixty-nine patients (training dataset) were used for model building and a separate 86 patients (test dataset) for model validation. A fraction of tumor cells sensitive to each drug was incorporated as a model parameter, and T was assumed as cytostatic and X/F and P as cytotoxic. Cox proportional hazards analyses were performed on model parameters and patient covariates. The model well described the time course of observed tumor size changes, and revealed that the pretreatment tumor growth rate constant kg, which was formulated as a function of pretreatment disease duration and baseline tumor size, was positively correlated with baseline tumor size (p = 0.0084) and histologic grade (p = 0.034), and the efficacy of 5-FU with body weight (p < 2e−16) and that of cisplatin with histologic grade (p = 0.00013). Prior gastrectomy and Eastern Cooperative Oncology Group scores were significant prognostic factors for progression-free survival (PFS). For hazards analysis, a unit increase of kg was associated with a relative risk of 3.19 for PFS (p = 0.00055) and 4.45 for OS (p = 2e−04) in the test dataset, with a similar trend observed in the training dataset. Dose-response simulations showed that, for small baseline tumor size or low histologic grade, a maximum cytotoxic effect was attainable with a dose smaller than the current recommended dose.

KEY WORDS

dose-response model HER2-positive gastric cancer prediction model trastuzumab tumor progression model 

Notes

Acknowledgements

This work was supported by a grant from the Brain Korea 21 PLUS Project for Medical Science, Yonsei University.

Compliance with Ethical Standards

The study protocol was approved by the Institutional Review Board of Severance Hospital and was identical to that of the ToGA clinical trial, except that, for patients enrolled after year 2012, RECIST version 1.1 was used (12) instead of Version 1.0.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12248_2018_223_MOESM1_ESM.docx (39 kb)
ESM 1 (DOCX 39 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Dongwoo Chae
    • 1
    • 2
  • Chung Mo Nam
    • 3
  • Joo Hoon Kim
    • 4
  • Choong-Kun Lee
    • 5
    • 6
  • Seung-Seob Kim
    • 7
  • Hyo Song Kim
    • 5
    • 6
  • Minkyu Jung
    • 5
    • 6
  • Jae Ho Cheong
    • 6
    • 8
  • Hyun Cheol Chung
    • 5
    • 6
  • Sun Young Rha
    • 5
    • 6
  • Kyungsoo Park
    • 1
  1. 1.Department of PharmacologyYonsei University College of MedicineSeoulSouth Korea
  2. 2.Brain Korea 21 PLUS Project for Medical ScienceYonsei UniversitySeoulSouth Korea
  3. 3.Department of Preventive Medicine and Public HealthYonsei University College of MedicineSeoulSouth Korea
  4. 4.Department of OncologyGood Morning HospitalPyeongtaek-siSouth Korea
  5. 5.Division of Medical Oncology, Department of Internal MedicineYonsei University College of MedicineSeoulSouth Korea
  6. 6.Song-Dang Institute for Cancer ResearchYonsei University College of MedicineSeoulSouth Korea
  7. 7.Department of RadiologyYonsei University College of MedicineSeoulSouth Korea
  8. 8.Department of General SurgeryYonsei University College of MedicineSeoulSouth Korea

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