Page 195 - 20dynamics of cancer

180 CHAPTER 9

First, the ability of two-stage models to fit the data provides rela-
tively little insight: with enough parameters and a mathematically flex-
ible formulation, a model can be molded to a wide variety of data. Sec-
ond, qualitative genetic evidence points to several rate-limiting steps in
most adult-onset cancers (Chapter 3), although those data are not con-
clusive. Third, to explain the high observed exponents on age or dura-
tion, one must typically assume that clonal expansion is slow and steady
over many years; bursts of clonal expansion over shorter periods do not
match the observations so easily. Fourth, clonal expansion is more dif-
ficult to test experimentally than models that emphasize simple genetic
or epigenetic changes to cells, because genomic changes can be manip-
ulated and compared between treatments more easily than properties
of clonal expansion.
The two-stage model may be limited and difficult to test. However,
aspects of clonal expansion in multistage progression may play an im-
portant role in the patterns of incidence (Luebeck and Moolgavkar 2002).
To move ahead, this idea requires useful comparative hypotheses that
predict different outcomes based on measurable differences in the dy-
namics of clonal expansion.

SUMMARY
Several theories fit the observed relatively low exponent on dosage
and high exponent on duration. But a close fit by itself provides little
evidence to distinguish one theory from another. Rather, one should
use the alternative theories and fits to the data as a first step toward
developing biologically plausible hypotheses and their quantitative con-
sequences. Once those theories are understood, one can then try to
formulate comparative tests that discriminate between the alternatives.
I turn to potential comparative tests after I discuss a related topic in
chemical carcinogenesis.

9.2 Cessation of Carcinogen Exposure

Lung cancer incidence of continuing smokers increases with approx-
imately the fourth or fifth power of the duration of smoking (Doll and
Peto 1978). By contrast, incidence among those who quit remains rela-
tively flat after the age of cessation (Doll 1971; Peto 1977; Halpern et al.
1993).