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The AAPS Journal

, 21:27 | Cite as

Estimation of Solid Tumor Doubling Times from Progression-Free Survival Plots Using a Novel Statistical Approach

  • Katherine Kay
  • Keith Dolcy
  • Robert Bies
  • Dhaval K. ShahEmail author
Research Article

ABSTRACT

Tumor doubling time can significantly affect the outcome of anticancer therapy, but it is very challenging to determine. Here, we present a statistical approach that extracts doubling times from progression-free survival (PFS) plots, which inherently contains information regarding the growth of solid tumors. Twelve cancers were investigated and multiple PFS plots were evaluated for each type. The PFS plot showing fastest tumor growth was deemed to best represent the inherent growth kinetics of the solid tumor, and selected for further analysis. The exponential tumor growth rates were extracted from each PFS plot, along with associated variabilities, which ultimately allowed for the estimation of solid tumor doubling times. The mean simulated doubling times for pancreatic cancer, melanoma, hepatocellular carcinoma (HCC), renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, hormone receptor positive (HR+) breast cancer, human epidermal growth factor receptor-2 positive (HER-2+) breast cancer, gastric cancer, glioblastoma multiforme, colorectal cancer, and prostate cancer were 5.06, 3.78, 3.06, 2.67, 2.38, 2.40, 4.31, 4.12, and 3.84 months, respectively. For all cancers, clinically reported doubling times were within the estimated ranges. For all cancers, except HCC, the growth rates were best characterized by a log-normal distribution. For HCC, the gamma distribution best described the data. The statistical approach presented here provides a qualified method for extracting tumor growth rates and doubling times from PFS plots. It also allows estimation of the distributional characteristics for tumor growth rates and doubling times in a given patient population.

KEY WORDS

PK/PD modeling and simulation preclinical-to-clinical translation progression-free survival solid tumor doubling time tumor growth rate 

Notes

FINANCIAL SUPPORT

This work was supported by NIH grant GM114179 and AI138195 to D.K.S., and the Centre for Protein Therapeutics at University at Buffalo.

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of Interest

RB has served as an expert witness through Belmore Neidrauer LLP funded by Janssen Pharmaceutical. All other authors declare they have no competing interests.

Supplementary material

12248_2019_302_MOESM1_ESM.docx (1.2 mb)
ESM 1 (DOCX 1196 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Katherine Kay
    • 1
    • 2
  • Keith Dolcy
    • 1
  • Robert Bies
    • 1
  • Dhaval K. Shah
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesThe State University of New York at BuffaloBuffaloUSA
  2. 2.Metrum Research GroupTariffvilleUSA

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