John T. Flannery

Risk of leukemia after chemotherapy and radiation treatment for breast cancer

BACKGROUND Few studies have evaluated the late effects of adjuvant chemotherapy for breast cancer. Moreover, the relation between the risk of leukemia and the amount of drug given and the interaction of chemotherapy with radiotherapy have not been described in detail. METHODS We conducted a case-control study in a cohort of 82,700 women given a diagnosis of breast cancer from 1973 to 1985 in five areas of the United States. Detailed information about therapy was obtained for 90 patients with leukemia and 264 matched controls. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose, 7.5 Gy). RESULTS The risk of acute nonlymphocytic leukemia was significantly increased after regional radiotherapy alone (relative risk, 2.4), alkylating agents alone (relative risk, 10.0), and combined radiation and drug therapy (relative risk, 17.4). Dose-dependent risks were observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk, 31.4 vs. 3.1). There was little increase in the risk associated with total cyclophosphamide doses of less than 20,000 mg. CONCLUSIONS Although leukemia occurs in few patients with breast cancer, significantly elevated risks were linked to treatments with regional radiation and alkylating agents. Melphalan is a more potent leukemogen than cyclophosphamide or radiotherapy. Low risks were associated with the levels of cyclophosphamide in common use today. Systemic drug therapy combined with radiotherapy that delivers high doses to the marrow appears to enhance the risk of leukemia.

Cancer in the Contralateral Breast after Radiotherapy for Breast Cancer

BACKGROUND Patients with breast cancer have a threefold increase in the risk that a second breast cancer will develop. Radiation treatment for the initial cancer can result in moderately high doses to the contralateral breast, possibly contributing to this heightened risk. METHODS We conducted a case-control study in a cohort of 41,109 women diagnosed with breast cancer between 1935 and 1982 in Connecticut. We reviewed the medical records of 655 women in whom a second breast cancer developed five or more years after the initial tumor and compared their radiation exposure with that of 1189 matched controls from the cohort who did not have a second cancer. The dose of radiation to the contralateral breast was estimated from the original radiotherapy records. Among the exposed women, the average radiation dose to the contralateral breast was 2.82 Gy (maximum, 7.10). RESULTS Overall, 23 percent of the women who had a second breast cancer and 20 percent of the controls had received radiotherapy (relative risk of a second breast cancer associated with radiotherapy, 1.19). Among women who survived for at least 10 years, radiation treatment was associated with a small but marginally significant elevation in the risk of a second breast cancer (relative risk, 1.33); the risk increased significantly with the dose of radiation. An increase in risk in association with radiotherapy was evident only among women who were under 45 years of age when they were treated (relative risk, 1.59) and not among older women (relative risk, 1.01). CONCLUSIONS Radiotherapy for breast cancer contributes little to the already high risk of a second cancer in the opposite breast. Fewer than 3 percent of all second breast cancers in this study could be attributed to previous radiation treatment; the risk, however, was significantly increased among women who underwent irradiation at a relatively young age (less than 45 years). Radiation exposure after the age of 45 entails little, if any, risk of radiation-induced breast cancer.

Central nervous system tumors in children cns tumors in children

Of 488 central nervous system neoplasms occurring in children over a 39‐year period, 467 were intracranial and 21 were intraspinal. The most common intracranial neoplasms were astrocytoma (28%), medulloblastoma (25%), ependymal neoplasm (9%), craniopharyngioma (9%), and glioblastoma multiforme (9%). The median age at diagnosis was 6 years with a male‐to‐female ratio of 1.3:1. Overall mean survival was 53.4 months and varied greatly relative to the type of tumor and the location. Of the intraspinal neoplasms the most frequently noted were the astrocytoma (47%) and the ependymal neoplasm (24%). The median age at diagnosis was 10 years with a male‐to‐female ratio of 1:1. The average survival from diagnosis (54.1 months) was comparable to that of intracranial neoplasms. Detailed analyses of each histological type of tumor relative to age at diagnosis, sex, anatomical location and survival from diagnosis are reported for both intracranial and intraspinal neoplasms. Cancer 40:3123‐3132, 1977.

Genetic Disease in Offspring of Long-Term Survivors of Childhood and Adolescent Cancer

Numerous case series have addressed the concern that cancer therapy may damage germ cells, leading to clinical disease in offspring of survivors. None has documented an increased risk. However, the methodological problems of small series make it difficult to draw firm conclusions regarding the potential of cancer treatments to damage the health of future offspring. We conducted a large interview study of adult survivors of childhood cancer treated before 1976. Genetic disease occurred in 3.4% of 2,198 offspring of survivors, compared with 3.1% of 4,544 offspring of controls (P=.33; not significant); there were no statistically significant differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. A comparison of survivors treated with potentially mutagenic therapy with survivors not so treated showed no association with sporadic genetic disease (P=.49). The present study provides reassurance that cancer treatment using older protocols does not carry a large risk for genetic disease in offspring conceived many years after treatment. With 80% power to detect an increase as small as 40% in the rate of genetic disease in offspring, this study did not do so. However, we cannot rule out the possibility that new therapeutic agents or specific combinations of agents at high doses may damage germ cells.

Second primary cancer after treatment for cervical cancer. An international cancer registries study

Background. The pattern of second cancers after treatment for cervical cancer provides important information on the risk of radiation‐induced malignancies. Large numbers of women survive many years and can be studied for late effects.

Time trend and the age-period-cohort effect on the incidence of histologic types of lung cancer in Connecticut, 1960-1989.

Background. Recent epidemiologic studies have suggested changing patterns of lung cancer incidence by histologic type. The observed time trends have been attributed to a change in the rate of cigarette smoking, changes in exposure to new environmental carcinogens, and changes in the criteria for the histopathologic diagnosis of lung cancer. The current study was designed to examine the incidence patterns of lung cancer by histologic type in Connecticut and to use this information to project the future trend of the disease in this population.

Continuing increase in incidence of germ-cell testis cancer in young adults: Experience from Connecticut, USA, 1935–1992

The current study is designed to examine long‐term trends by histologic types of testis cancer in Connecticut. A regression model was used to identify age, period, or cohort as determinants of the time‐trend on histologic types of testis cancer. The results from this descriptive epidemiologic study show that the overall age‐adjusted incidence rate of testis cancer has increased 3.5‐fold in Connecticut during the past nearly 60 years of cancer registration. The rates for seminoma and nonseminoma have been increasing since the mid‐1950s and increase in a similar manner for those aged 15 to 49. The largest increase was observed in the age groups 20 to 44 for seminoma and 15 to 34 for non‐seminoma. The observed increase was limited to whites. The results from age‐period‐cohort modeling suggest that the observed increase in seminoma before 1950s could be largely attributable to a period effect, while the increase for cohorts born after about 1910 both for seminoma and for non‐seminoma are mainly explained by a strong birth‐cohort effect. Therefore, the observed increase in germ‐cell testis cancer in this population is likely to continue in the coming years. Thus far, the proposed hypotheses, such as exposure to DES in utero, earlier lifetime exposures to viruses, trauma or unusual amounts of heat to the testis, cannot adequately explain the observed incidence patterns of testis cancer. Analytical epidemiologic studies with large sample size are urgently needed to examine the risk factors responsible for the increase.

Cancer in Relatives of Children with Central-Nervous-System Neoplasms

We compared the occurrence of cancer in parents, siblings, and offspring of 643 patients who had central-nervous-system tumors in childhood (cases), as recorded in the Connecticut Tumor Registry, with the occurrence in parents, siblings, and offspring of 360 controls selected according to birth certificate and matched for sex, birth date, and birthplace. Overall cancer incidence was comparable in the two groups. However, 11 nervous-system tumors occurred in relatives of cases, whereas none occurred in relatives of controls (P = 0.0005). Nine relatives of cases but no relatives of controls had cancer of the hematopoietic-lymphatic system (P = 0.003). Nine siblings of cases but only one sibling of a control had cancer as children. Medulloblastoma and glioblastoma multiforme were overrepresented in the group of children whose relatives had central-nervous-system tumors. We compared the actual number of cancers of the central nervous system or hematopoietic-lymphatic system in relatives of cases with the number expected on the basis of known incidence rates and found a fivefold excess. We conclude that the occurrence of a brain tumor in a child is a marker for an increased likelihood of central-nervous-system tumors, leukemia, and childhood tumors in the family.

Epidemiology of non-Hodgkin lymphoma in Connecticut : 1935-1988

Background. During the past decades, there have been reports of increases in the incidence and mortality rates due to non‐Hodgkin lymphoma (NHL) in many parts of the world. The risk factors responsible for the increasing incidence are largely unknown. This study provided an overview of the incidence pattern of NHL in Connecticut and generated hypotheses for additional investigation.

The time trend and age-period-cohort effects on incidence of adenocarcinoma of the stomach in Connecticut from 1955-1989

Background. Adenocarcinoma of the gastric cardia has been be increasing in Connecticut, and the risk factors responsible for the increasing incidence are unknown. This study examined the incidence pattern of adenocarcinoma of the gastric cardia and distal stomach in Connecticut during the past decades and identified components of birth cohort, period, and age as determinants of the observed time trends by regression modeling.