cellular radiosensitivity in such radiotherapy patients have, so far, failed to reveal evidence of strong correlations between in vivo and in vitro responses although subsets of these patients do show statistically significant increases in cellular radiosensitivity under some assay conditions (Burnet and others 1998). Similarly limited molecular studies show no correlation between adverse reactions to radiotherapy and heterozygous ATM gene mutation (Appleby and others 1997; Burnet and others 1998). The question as to whether adverse tissue reaction to radiotherapy signals potentially increased risk of therapy-related second tumors has yet to be addressed in epidemiologic studies.

Postradiotherapy observations on specific sets of cancer patients have, however, revealed valuable information on genetic associations with risk of second tumors (Meadows 2001). These data are summarized and referenced in Table 3-6. In brief, there is evidence of an excess of radiotherapy (RT)-related tumors in the human cancer-prone conditions heritable retinoblastoma, NBCCS, and LFS plus related conditions, as well as in children from families with a history of early onset cancer. In addition there are reports suggesting that neurofibromatosis is a positive factor for RT-related tumorigenesis (Robison and Mertens 1993). By contrast, a variety of studies discussed by Mark and colleagues (1993) provide no clear evidence that genetic factors are important for RT-related breast cancer. Recent studies provide no evidence that the status of BRCA genes influences post-radiotherapy outcomes at 5 years (Pierce and others 2000).

In Table 3-6 the data suggesting that NBCCS and LFS patients have substantial increases in tumorigenic radiosensitivity are in accord with data obtained experimentally with their rodent genetic homologues. For retinoblastoma (RB), the large size of the U.S.-based epidemiologic studies of Eng and colleagues (1993) and Wong and coworkers (1997a) allows some judgments to be developed on the degree to which this suppressor gene disorder predisposes to (second) radiogenic soft-tissue sarcoma and bone cancer. Although there is a clear dose-response for radiation tumorigenesis, these data imply that excess relative risk (ERR) in heritable RB patients may be lower than in the nonheritable controls.

The background rate of tumorigenesis in RB is, as expected, rather high, and for the purposes of this report, excess absolute risk (EAR) may be a more useful measure of tumorigenic radiosensitivity than ERR. In considering this issue, the ICRP (1998) and NRPB (2000) suggest that the EAR in heritable RB is around fivefold higher than in the nonheritable group. It is notable that low values of ERR for radiogenic cancer in such cancer-prone conditions are consistent with other epidemiologic data on radiation tumorigenesis where high background cancer rates also tend to be accompanied by lower ERRs. Abramson and colleagues (2001) have also reported on third tumors in RB patients after radiotherapy. As might be expected, the sites of these additional tumors generally accorded with the irradiated volume of normal tissue.

In summary, although clinical and epidemiologic data on RT patients are limited, they are sufficient to confirm the view developed from mechanistic knowledge and experimental studies that human genetic susceptibility to spontaneous tumorigenesis is often accompanied by an increase in absolute cancer risk after ionizing radiation. Quantifying that risk is problematical, but the single study on RB patients that has this capacity is suggestive of relatively modest (about fivefold) increases over that of normal individuals. In the

TABLE 3-6 Postradiotherapy Observations on Risk of Second Tumors in Humans

Genetic Disorder or Study Group

First Tumor


Key References



Excess bone tumors and soft-tissue sarcomas, large cohorts; some dose, dose-response, and risk estimates possible

Tucker and others (1987a)

Eng and others (1993)

Wong and others (1997a)

Abramson and others (2001)



Excess basal cell skin neoplasms and ovarian fibromas, short latency; case reports only

Strong (1977)

Southwick and Schwartz (1979)

LFS and related conditions


Follow-up of children developing posttherapy soft-tissue sarcoma, bone tumors, and acute leukemia—linkage with family histories of cancer

Strong and Williams (1987)

Heyn and others (1993)

Robison and Mertens (1993)

Malkin (1993)

Case-control study of therapy-related second tumors


Excess posttherapy tumors in children from non-LFS families with a history of early onset cancer

Kony and others (1997)

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