Page 196 - 20dynamics of cancer

CARCINOGENS 181

In 1977, Richard Peto (1977) stated that the approximately constant
incidence rate after smoking ceases “is one of the strongest, and hence
most useful, observational restrictions on the formulation of multistage
models for lung cancer.” Peto argued that, in any model, the observed
constancy in incidence after smoking has stopped “suggests that smok-
ing cannot possibly be acting on the final stage” of cancer progression.
There could, for example, be a particular gene or pathway that acts
as a final barrier in progression and resists the carcinogenic effects of
cigarette smoke.
In 2001, Julian Peto (2001) reiterated Richard’s argument: “The rapid
increase in the lung cancer incidence rate among continuing smokers
ceases when they stop smoking, the rate remaining roughly constant
for many years in ex-smokers (Halpern et al. 1993). The fact that the
rate does not fall abruptly when smoking stops indicates that the mys-
terious final event that triggers the clonal expansion of a fully malignant
bronchial cell is unaffected by smoking, suggesting a mechanism involv-
ing signaling rather than mutagenesis.”
In this section, I discuss which stages of progression may be affected
by the carcinogens in cigarette smoke. I begin by summarizing observa-
tions on how cancer incidence changes after the cessation of carcinogen
exposure. I then consider two alternative explanations. First, the car-
cinogen may affect only a subset of stages in cancer progression; the
particular stages affected determine how patterns of incidence change
after cessation. Second, the carcinogen may affect all stages of pro-
gression; the different precancerous stages at which individuals cease
exposure determine how patterns of incidence change after cessation.
Both models fit the data reasonably well.
As we have seen often, fitting by itself does not strongly distinguish
between competing hypotheses. I therefore introduce some compara-
tive approaches that may provide a better way to test alternatives.

OBSERVATIONS
Figure 9.8a shows the flattening of the incidence curve upon cessation
of smoking from data collected in the Cancer Prevention Study II of the
American Cancer Society (Stellman et al. 1988). This figure summarizes
data for 117,455 men who never smoked, 91,994 current smokers, and
136,072 former smokers. The top curve represents lifetime smokers