Context Second cancer is the leading cause of death in long-term survivors of
Hodgkin disease (HD), with exceptionally high risks of breast cancer among
women treated at a young age. Quantitative associations between radiotherapy
dose delivered to the breast and administered chemotherapy have not been reported
to date in large series, nor has the influence of ovarian exposures on subsequent
Objective To quantify the long-term risk of breast cancer associated with use
of radiotherapy and chemotherapy to treat young women with HD.
Design, Setting, and Subjects Matched case-control study of breast cancer within a cohort of 3817
female 1-year survivors of HD diagnosed at age 30 years or younger, between
January 1, 1965, and December 31, 1994, and within 6 population-based cancer
registries. The study was conducted March 1, 1996, through September 30, 1998.
Main Outcome Measures Relative risk (RR) of breast cancer associated with radiation dose delivered
to site of breast cancer or to ovaries and with cumulative dose of alkylating
Results Breast cancer occurred in 105 patients with HD who were matched to 266
patients with HD but without breast cancer. A radiation dose of 4 Gy or more
delivered to the breast was associated with a 3.2-fold (95% confidence interval
[CI], 1.4-8.2) increased risk, compared with the risk in patients who received
lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4)
with a dose of more than 40 Gy (P<.001 for trend).
Radiation risk did not vary appreciably by age at exposure or reproductive
history. Increased risks persisted for 25 or more years following radiotherapy
(RR, 2.3; 95% CI, 0.5-16.5; P = .03 for trend with
dose). Treatment with alkylating agents alone resulted in a reduced risk (RR,
0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and
radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast
cancer decreased with increasing number of alkylating agent cycles (P = .003 for trend). Risk also was low (RR, 0.4; 95% CI,
0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared
with those who received lower doses.
Conclusions Hormonal stimulation appears important for the development of radiation-induced
breast cancer, as evidenced by the reduced risk associated with ovarian damage
from alkylating agents or radiation. The high radiation-related risk, which
did not diminish at the highest doses or the longest follow-up, however, suggests
the need for lifetime surveillance and programs of patient and public awareness.