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Second Cancers After Fractionated Radiotherapy: Stochastic Population Dynamics EffectsWhen ionizing radiation is used in cancer therapy it can induce second cancers in nearby organs. Mainly due to longer patient survival times, these second cancers have become of increasing concern. Estimating the risk of solid second cancers involves modeling: because of long latency times, available data is usually for older, obsolescent treatment regimens. Moreover, modeling second cancers gives unique insights into human carcinogenesis, since the therapy involves administering well characterized doses of a well studied carcinogen, followed by long-term monitoring. In addition to putative radiation initiation that produces pre-malignant cells, inactivation (i.e. cell killing), and subsequent cell repopulation by proliferation can be important at the doses relevant to second cancer situations. A recent initiation/inactivation/proliferation (IIP) model characterized quantitatively the observed occurrence of second breast and lung cancers, using a deterministic cell population dynamics approach. To analyze ifradiation-initiated pre-malignant clones become extinct before full repopulation can occur, we here give a stochastic version of this I I model. Combining Monte Carlo simulations with standard solutions for time-inhomogeneous birth-death equations, we show that repeated cycles of inactivation and repopulation, as occur during fractionated radiation therapy, can lead to distributions of pre-malignant cells per patient with variance >> mean, even when pre-malignant clones are Poisson-distributed. Thus fewer patients would be affected, but with a higher probability, than a deterministic model, tracking average pre-malignant cell numbers, would predict. Our results are applied to data on breast cancers after radiotherapy for Hodgkin disease. The stochastic IIP analysis, unlike the deterministic one, indicates: a) initiated, pre-malignant cells can have a growth advantage during repopulation, not just during the longer tumor latency period that follows; b) weekend treatment gaps during radiotherapy, apart from decreasing the probability of eradicating the primary cancer, substantially increase the risk of later second cancers.
Document ID
20100039450
Acquisition Source
Johnson Space Center
Document Type
Reprint (Version printed in journal)
Authors
Sachs, Rainer K.
(California Univ. Berkeley, CA, United States)
Shuryak, Igor
(Columbia Univ. New York, NY, United States)
Brenner, David
(Columbia Univ. New York, NY, United States)
Fakir, Hatim
(Salzburg Univ. Austria)
Hahnfeldt, Philip
(Tufts Univ. Boston, MA, United States)
Date Acquired
August 25, 2013
Publication Date
December 7, 2007
Publication Information
Publication: Journal of Theoretical Biology
Volume: 249
Issue: 3
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: NNJ06HA27G
CONTRACT_GRANT: P41-EB-002033
CONTRACT_GRANT: CA78496
CONTRACT_GRANT: DEFG02-03ER63668
CONTRACT_GRANT: F16R-CT-2003-508842
CONTRACT_GRANT: NSCOR04-0014-0017
CONTRACT_GRANT: 03-OBPR-07-0059-0065
Distribution Limits
Public
Copyright
Other

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