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Tumor Growth Instability and Its Implications for Chemotherapy

¹ Dipartimento di Fisica, Università di Catania, ² Istituto Nazionale Fisica Nucleare-Catania, and ³ Centro Siciliano Fisica Nucleare e Struttura della Materia, Catania, Italy; ⁴ Istituto Oncologico del Mediterraneo, Viagrande, Italy; ⁵ Dipartimento Neuroscienze, Torino University; ⁶ CNISM Torino University e Politecnico, Torino, Italy; and ⁷ Complex Biosystems Modeling Laboratory, Harvard-MIT (HST), Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts

Requests for reprints: Paolo Castorina, Dipartimento di Fisica Univeristà di Catania, Via Santa Sofia 64, 95100 Catania, Italy. Phone: 39-095-378-5322; Fax: 39-095-378-5231; E-mail: paolo.castorina{at}ct.infn.it.

Optimal delivery of chemotherapy intensity is dependent on host- and tumor-specific characteristics. In this article, the chemotherapy late intensity schedule is revised to account for tumor growth instability, where a small tumor cell fraction emerges that exhibits a higher proliferation rate than the parent strain. Modeling this instability as simplified two-population dynamics, we find that: (a) if this instability precedes the onset of treatment, the slope of the linear increase of the drug concentration for the standard "Norton-Simon late intensity schedule" changes and the initial value of the dose strongly depends on the ratio of the two tumor cell populations and on their distinct growth rates; and (b) if the instability trails the initial treatment, the effective chemotherapeutic drug concentration changes as well. Both cases point toward testable potential refinements of the Norton-Simon late intensity schedule. [Cancer Res 2009;69(21):8507–15]

Key Words: chemotherapy • survival probability • tumor instability