Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease.
BACKGROUND
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 risk.


OBJECTIVE
To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.


METHODS
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.


METHODS
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 agents.


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.
Travis
Lois B
LB
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md 20892 , USA. TravisL@mail.nih.edu
Hill
Deirdre A
DA
Dores
Graça M
GM
Gospodarowicz
Mary
M
van Leeuwen
Flora E
FE
Holowaty
Eric
E
Glimelius
Bengt
B
Andersson
Michael
M
Wiklund
Tom
T
Lynch
Charles F
CF
Van't Veer
Mars B
MB
Glimelius
Ingrid
I
Storm
Hans
H
Pukkala
Eero
E
Stovall
Marilyn
M
Curtis
Rochelle
R
Boice
John D
JD
Gilbert
Ethel
E
D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D001940:Breast / Q000528:radiation effects; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000209:etiology; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology*; D016609:Neoplasms, Second Primary / Q000453:epidemiology*; D010053:Ovary / Q000528:radiation effects; D011879:Radiotherapy Dosage; D012306:Risk
D018906:Antineoplastic Agents, Alkylating