Toward Risk-Based Breast Cancer Screening and Prevention Strategies for Survivors of Hodgkin's Lymphoma: One Step Closer?
Authors: Michael Crump
Journal: Journal of Clinical Oncology (2012)

Overall survival for Hodgkin’s lymphoma (HL) has improved significantly in the last 25 years, and the treatment of this curable malignancy has continued to evolve. Efforts to reduce the impact of late effects on long-term outcome have included moving therapy away from extensive use of alkylating agents, the replacement of extendedfield (mantle and subtotal nodal) radiation by combined-modality therapy by using chemotherapy plus involved-field radiation, and the recent evaluation of involved nodal irradiation to further reduce exposure of normal tissues to therapeutic radiation. The uptake of these changes is reflected in population-based data showing significantly less radiation therapy use in recent years and improved cause-specific survival of patients with HL. Recent data suggest that patients with limited-stage HL have improved overall survival when treated with chemotherapy alone, albeit at the cost of somewhat inferior diseasefree survival compared with a strategy that includes radiation. The legacy of curative extended-field radiation for HL is a large survivor population that is at an increased lifetime risk of second cancer, in particular breast, lung and GI cancer. Numerous studies have reported on breast cancer risk in survivors of HL and the many factors that can influence this risk. Age at time of treatment, size of radiation field, ovarian function after chemotherapy, and length of follow-up have all been shown to have a significant effect on the relative risk of developing breast cancer. This variability in risk is important in designing and evaluating screening strategies and in counseling women on their personal risk of a second cancer. The article by Swerdlow et al that accompanies this editorial offers additional information to address the challenge of individual risk assessment. They documented the clinical characteristics, treatment, and subsequent outcomes of 5,002 women with HL treated with supradiaphragmatic radiation (mantle-field in two thirds of the population) in England and Wales from 1956 to 2002. They used modeling to describe specific, cumulative breast cancer risk at given time points during follow-up according to age at diagnosis, treatment type (inclusion of alkylating agents or pelvic radiation), radiation dose, and time from first treatment. This is the largest cohort of survivors of HL yet evaluated for breast cancer risk, and the results reported confirm those of others: breast cancer risk is highest in women treated with mantle radiotherapy around puberty, decreases with increasing age at treatment (although still elevated for women treated in their thirties, the median age at diagnosis of HL in most countries), and decreases with smaller radiation field sizes and lower radiation doses. Gonadotoxic therapy (alkylating agents or radiation) reduced subsequent breast cancer risk but only for women treated after age 20 years. The cumulative absolute risks of breast cancer in this report are similar to those from another population-based study reported by Travis et al, who captured breast cancers reported in survivors of HL from several countries and compared this incidence with that of the US Surveillance, Epidemiology, and End Results population. These authors also modeled cumulative risk depending on dose of radiation, alkylator chemotherapy exposure, and duration of follow-up for women at different ages at diagnosis. The results from the current United Kingdom study are similar to those reported by Travis et al: the cumulative risk of breast cancer in a woman between ages 20 and 24 years at the time of treatment with supradiaphragmatic radiation and alkylator agent chemotherapy is 3.6% at 20 years and 11.5% at 40 years in the report by Swerdlow et al compared with 4.4% at 20 years and 12.5% at 30 years in the report by Travis et al. The report by Swerdlow et al extends the observations regarding risk over time and points out the significant increase in cumulative risk of breast cancer to at least 40 years of follow-up. They show that the absolute excess risk (AER) of breast cancer (cases per 10,000 in the population) continues to increase after 20 years of follow-up as the incidence of breast cancer in the general population increases with age. AER is a better measure of disease burden in the population and the extent of additional morbidity or mortality than standardized incidence ratios (SIRs; observed over expected number of cases). In the report by Swerdlow et al, AER increased with duration of follow-up and is more than twice the rate after 30 to 34 years of follow-up than the rate after 15 to 19 years post-treatment, whereas the SIRs fall with longer follow-up, reflecting the increasing incidence of breast cancer in the general United Kingdom population. The modeling data in this report also provide specific estimates of risk at a time period in the future according to the duration of time since treatment was received; for example, estimated risk over the next 15 years for a woman who had already been observed for 10 years. Although these data come from modeling, they do provide new information that leads to an important conclusion: breast cancer risk, although modified by several known JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 22 AUGUST 1 2012