A Prediction Model of Tumor Progression and Survival in HER2-Positive Metastatic Gastric Cancer Patients Treated with Trastuzumab and Chemotherapy
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 WORDSdose-response model HER2-positive gastric cancer prediction model trastuzumab tumor progression model
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.
- 1.Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.CrossRefPubMedGoogle Scholar
- 3.Chau I, Norman AR, Cunningham D, Waters JS, Oates J, Ross PJ. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer—pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol. 2004;22(12):2395–403.CrossRefPubMedGoogle Scholar
- 5.Pozzo C, Ohashi Y, project G. Meta-analyses of randomized trials assessing the influence of chemotherapy and prognostic factor in advanced/recurrent gastric cancer. J Clin Oncol. 2009;27(15_suppl):4550.Google Scholar
- 6.Lee H, Yuh Y, Kim S. Serum lactate dehydrogenase (LDH) level as a prognostic factor for the patients with advanced gastric cancer. J Clin Oncol. 2009;27(15_suppl):e15621.Google Scholar
- 8.Cremolini C, Loupakis F, Antoniotti C, Lonardi S, Masi G, Salvatore L, et al. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015;26(6):1188–94.CrossRefPubMedGoogle Scholar
- 9.Tsuji A, Sunakawa Y, Ichikawa W, Nakamura M, Kochi M, Denda T, et al. Early tumor shrinkage and depth of response as predictors of favorable treatment outcomes in patients with metastatic colorectal cancer treated with FOLFOX plus cetuximab (JACCRO CC-05). Target Oncol. 2016;11:799–806.CrossRefPubMedGoogle Scholar
- 19.Santos C, Morgan BW, Geller RJ. The successful treatment of 5-fluorouracil (5-FU) overdose in a patient with malignancy and HIV/AIDS with uridine triacetate. Am J Emerg Med. 2016.Google Scholar