Medical exposures have relevance in two ways. Firstly, they may increase the risk of the primary cancer. An excellent case in point is the association, recently noted, between extreme prematurity and risk of hepatoblastoma. This association appears to be new, strongly suggesting that liver cancer arises as a result of a specific perinatal-ICU intervention that has been introduced in the last decade or so.

Perhaps no group has more to be concerned about the potential for adverse effects of medical exposures than survivors of childhood cancer. Many have been exposed to very high level (often, near-lethal) doses of agents that are potent mutagens and carcinogens, including radiation and alkylating agents. Unlike adults with cancer, most of whom are exposed towards the end of their natural life span, these children potentially have many decades of life ahead of them - long enough for the development of a wide range of cardiac, neurological, endocrine, reproductive, cognitive, malignant, and other complications and adverse effects.

Studies on medical exposures which Childhood Cancer Core members have either conducted or contributed significantly to over the last five years are listed on the top.

Over the last decade, it has become apparent that prematurity is a very strong risk factor for hepatoblastoma. The reasons for this are unclear, but suspicion must fall on factors the premature infant is exposed to in the neonatal ICU, particularly any treatments that have come into widespread use over the last decade. The study examines whether the exposures that accompany prematurity and its treatment are risk factors for hepatoblastoma.

Project A: Second Malignancy Following Hodgkin's Disease

Survivors of childhood Hodgkin's disease (HD) from the Late Effects Study Group (15 institutions from the US, Canada and Western Europe) were followed for SMNs and associated risk factors. The risk of solid tumors, especially breast cancer was increased in women who were treated with radiation for childhood Hodgkin's disease. The study concluded that systematic screening for breast cancer could be important in the health care of such women.

A follow-on project involves (a) Construction of pedigrees of patients with breast cancer following Hodgkin's disease, (b) Identification of mutations (germline/somatic) in candidate genes (p53, ATM, BRCA1) in these patients matched controls, (c) Institution of a protocol for annual screening in female and (d) Expansion of the HD cohort.

In another study, members of the International Society of Pediatric Oncology are registering patients with HD (diagnosed before 21) and who subsequently developed a SMN, for comparison with HD patients who do not have a SMN.

2150 recipients of BMT at the University of Minnesota were studied to determine the incidence of post-BMT malignant neoplasms. The estimated actuarial incidence of any post-BMT malignancy was 9.9% + 2.3% at 13 years post-transplant (SIR: 11.6, 95% CI, 8.2-14.5).

In a second study, at the City of Hope, the cumulative probability of SMN in 1858 patients who had undergone BMT was 12.6%, 15 years from transplant.

Project C: Second Neoplasms Following Childhood ALL

A cohort of 3711 patients with ALL, treated by CCG institutions, was followed to determine the incidence of SMN and associated risk factors. The cumulative probability of developing an SMN was 1.3% at 13 years. The overall conclusion was that this low rate represents an acceptable risk for children with ALL. Manuscript in preparation.

Project D: Second Malignant Neoplasms Following Childhood Cancer: Possible Interactions Between Genetic Predisposition and Treatment

Funding has been received to identify and characterize all second neoplasms developing among patients treated according to the CCG protocols. The study will include identification of cases, construction of pedigrees, correlation with sociodemographic, clinical and treatment characteristics, and banking of tumor and blood specimens.

This study utilizes a new quality-of-life instrument [Minneapolis-Manchester Quality of Life (MM-QOL)] for childhood cancer survivors, and assess the feasibility of incorporating this instrument into a variety of clinical trials.

Project B: Long-Term Follow-up of Survivors of Bone Marrow Transplantation

This is a collaboration between City of Hope and the University of Minnesota to define a cohort of 955 patients with BMT and who have survived at least five years. The objective is (i) to identify treatment factors and survivor characteristics associated with an increased risk of late death; ii) to determine incidence of, and risk factors for, specific long term sequelae (iii) and to assess quality of life and health-related behaviors in these patients.

Project C: Survival Following Childhood ALL: Ethnicity as a Risk Factor

Survival rates by ethnic background were compared for 8,762 children and adolescents younger than 21 years of age with newly diagnosed ALL registered on one of the 12 CCG protocols from 1983 to 1995. Analysis revealed highly significant differences among ethnic groups (p<0.0001) - Asians had the best outcome, African-Americans the poorest, and the outcome for the Hispanic children was intermediate between Caucasians and the African-Americans.

Project D: Long-term Effects of Cancer Treatment in Identical Twins

Six pairs of identical twins have been studied in a pilot program to evaluate the use of twins in assessing long-term effects of treatment. For many outcome measures, such as cognitive function, reproductive effects, growth and development, etc, there are no simple 'population norms' that can be usefully applied. However, an unaffected, genetically identical twin provides a near-perfect control, giving accurate information on what would have been expected for these measures, had the child not been exposed to cancer therapy. In the pilot study, the six pairs were evaluated with a brain MRI, a CT scan of bone density, a cardiac evaluation, a respiratory evaluation, and complete physical examination and comprehensive health questionnaire and a panel of psycho-cognitive measurements.

Project E: Quality of Life in Survivors of AML

This is a comparison of quality of life for children given either a bone marrow transplant or chemotherapy (on a pseudo-random basis, depending on the availability of an HLA matched sibling). Dr. Buckley is collaborating with the study's P.I. (Dr. Nicholson at Oregon Health Sciences University) in the design and analysis of this study.