Second Cancers Associated With Hodgkin’s Disease Treatment

ORLANDO—Treatments credited with improving 5-year survival rates for patients with childhood Hodgkin’s disease may lead to an increased risk of leukemia, breast cancer, and other neoplasms years later, according to a study by the Late Effects Study Group (LESG) presented at the American Society of Hematology annual meeting (abstract 3198).

Smita Bhatia, MD, MPH, director of Epidemiology and Outcomes Research, Pediatric Hematology and Oncology, City of Hope National Medical Center, Los Angeles, presented updated findings from a retrospective statistical analysis to determine the incidence of second cancers and the associated risk factors.

Prior studies had shown late effects of Hodgkin’s disease therapy, including second cancers, endocrine and pulmonary dysfunction, and cardiac compromise. "The most devastating of all is second cancers," Dr. Bhatia said. "There was a 7-fold to 10-fold increase, with females being at excess risk."

1,380 Hodgkin’s Disease Survivors

Dr. Bhatia’s team analyzed data from the clinical records of 1,380 Hodgkin’s disease survivors. Patients had been diagnosed in childhood, between 1955 and 1986. The median age at diagnosis was 11 years (range, 1 to 16). The LESG includes patients from 15 North American and European centers.

Median follow-up for this analysis was 15 years, with some patients followed for up to 45 years. Males comprised 65% of the group. Eight percent had received only chemotherapy, 23% had received only radiation therapy, and 69% both.

A total of 146 patients developed a second cancer, 112 solid tumors, 28 leukemias, and 6 non-Hodgkin’s lymphomas. A multivariate analysis showed that the relative risk of second cancers was greater for those diagnosed between ages 10 and 16, those who received both chemotherapy and radiation therapy, and those who had a recurrence.

Risk of Secondary Leukemia

The relative risk of developing a secondary leukemia increased for those treated with alkylating agents and for those with advanced-stage disease (stage III or IV) at the time of diagnosis. The risk reached a plateau after 14 years; 11% of the patients are alive.

The relative risk of solid tumors was greater for females, those diagnosed between ages 10 and 16, those who received both chemotherapy and radiation therapy, and those who had a recurrence.

Of the 112 solid tumors, 29 were breast, 19 thyroid, 17 basal cell, 7 colorec-tal, 5 lung, and 35 in other areas (see Figure below). One breast cancer occurred in a male patient.

For the cohort’s 29 breast cancer patients, the median age at Hodgkin’s disease diagnosis was 14 years and at breast cancer diagnosis, 32 years. The median time to breast cancer was 18 years. The median dose of mantle radiation received was 35 Gy. All patients developed their cancer within the radiation field. Multivariate analysis showed an increased relative risk for those who were 10 to 16 years of age at diagnosis and those who had radiation therapy; 86% of the patients are alive. "As the cohort approaches 25 to 30 years of age, the risk of secondary breast cancer increases," Dr. Bhatia said. "By 40 years of age, 25% are at risk of breast cancer."

The time to second cancer and cumulative probability at 30 years varied for other solid tumors: For thyroid cancer, 14 years and 6.7%, respectively; for colorectal cancer, 23 years and 4%; and for lung cancer, 24 years and 3%.

A total of 17 patients developed a third neoplasm, 8 of them breast cancers. The 10-year probability of a third neoplasm was 24%, and the median time to a third neoplasm was 5.8 years. Risk factors included female sex and radiation therapy.

All together, the cohort had an 18-fold increased risk of second cancers and a 54-fold increased risk of breast cancer, compared with the general population. Members of the cohort also were at greater risk for thyroid, colorectal, and lung cancer.

"Our most important findings were that we continue to see an increase in radiation-associated solid tumors and the emergence of adult onset cancers at a younger age than expected," Dr. Bhatia concluded. She noted the importance of early detection of second malignancies through appropriate surveillance and screening of this high-risk population.

Dr. Bhatia’s future research will evaluate the possible effects of other variables, such as oral contraceptives or estrogen replacement therapy, on the development of breast cancer in this cohort and the effects of smoking on the group’s lung cancer risk.