The Executive Committee of the Society of Toxicologic Pathology appointed an ad hoc
working group to review the current use of the Peto model for statistical analysis of
rodent carcinogenicity study data and to provide recommendations for pathologists
regarding appropriate and consistent classifi cation of neoplasms for analysis by the
Peto model. In the Peto model, neoplasms that are detected as in-life observations
are classifi ed as Mortality Independent and the incidences of these
neoplasms are analyzed by the onset-rate method. For neoplasms that are not detected
in-life in animals that come to necropsy before the end of the treatment period, the
original Peto model requires pathologists to classify neoplasms as
Fatal or Incidental (Non-fatal
). Each Fatal neoplasm is modeled statistically as rapidly fatal
regardless of how long the neoplasm has been present in the animal, and the date of
death is used as a surrogate for date of onset of Fatal neoplasms.
Fatal neoplasms are analyzed by the death-rate (life-table
analysis) method, while Incidental neoplasms are analyzed by the
prevalence method. In practice, most neoplasms that cause death are not rapidly
fatal, e.g., a slowly progressive pituitary adenoma in a rat. The Peto model does not
appropriately model slowly growing or slowly progressive neoplasms that cause
death.
Recommendations: 1. For animals that die or are killed prior to scheduled sacrifi ce,
all neoplasms should be classifi ed into one of four categories on an
animal-by-animal basis: Observed In Life
(Mortality-Independent)—Neoplasms that were observed during in-life observations and
for which the day of onset (fi rst observation) was recorded;
Incidental—Neoplasms that were not observed prior to necropsy and likely
did not contribute to death of the animal or bringing the animal to
necropsy; Rapidly Fatal —Neoplasms that were not observed prior to
necropsy, likely contributed to death or bringing an animal to necropsy, and appeared
to grow and develop rapidly. For these neoplasms, the day of death would serve as a
surrogate for the day of onset of the neoplasm; Not Rapidly
Fatal—Neoplasms that were not observed prior to necropsy, likely contributed
to death or bringing an animal to necropsy, and did not appear to grow or develop
rapidly. 2. Other guidelines for pathologists interpreting carcinogenicity studies
include: More than one neoplasm may be Rapidly Fatal, Not Rapidly
Fatal , and/or Incidental in a single animal. An individual
animal may have 2 or more Rapidly Fatal neoplasms if the pathologist
believes that each neoplasm had a rapid onset and likely contributed to bringing the
animal to necropsy; Each pathologist should use scientifi c judgment when
differentiating Rapidly Fatal and Not Rapidly Fatal
neoplasms. This scientifi c judgment is similar to that used in determining whether
neoplasms contribute to the cause of death. Criteria for malignancy (tissue invasion,
metastasis, necrosis, high mitotic index, anaplasia, etc.) can be helpful as guides
for classifying a neoplasm as Rapidly Fatal. 3. Industry and regulatory
statisticians should continue to explore alternatives to the Peto method that do not
require classifi cation of neoplasms according to their impact on the death of the
animal, and should use these methods if they offer equivalent or superior analytical
capabilities.
