Marilyn Stovall

Tumors of the brain and nervous system after radiotherapy in childhood.

We investigated the relation between radiotherapy in childhood for tinea capitis and the later development of tumors of the brain and nervous system among 10,834 patients treated between 1948 and 1960 in Israel. Benign and malignant tumors were identified from the pathology records of all Israeli hospitals and from Israeli national cancer and death registries. Doses of radiation to the neural tissue were retrospectively estimated for each patient (mean, 1.5 Gy). Sixty neural tumors developed in the patients exposed as children, and the 30-year cumulative risk (+/- SE) was 0.8 +/- 0.2 percent. The incidence of tumors was 1.8 per 10,000 persons per year. The estimated relative risk as compared with that for 10,834 matched general-population controls and 5392 siblings who had not been irradiated was 6.9 (95 percent confidence interval, 4.1 to 11.6) for all tumors and 8.4 (confidence interval, 4.8 to 14.8) when the analysis was restricted to neural tumors of the head and neck. Increased risks were apparent for meningiomas (relative risk, 9.5; n = 19), gliomas (relative risk, 2.6; n = 7), nerve-sheath tumors (relative risk, 18.8; n = 25), and other neural tumors (relative risk, 3.4; n = 9). A strong dose--response relation was found, with the relative risk approaching 20 after estimated doses of approximately 2.5 Gy. Our study confirms that radiation doses on the order of 1 to 2 Gy can significantly increase the risk of neural tumors.

Bone sarcomas linked to radiotherapy and chemotherapy in children

We estimated the risk of subsequent bone cancer among 9170 patients who had survived two or more years after the diagnosis of a cancer in childhood. As compared with the general population, the patients had a relative risk of 133 (95 percent confidence interval, 98 to 176) and a mean (+/- SE) 20-year cumulative risk of 2.8 +/- 0.7 percent. Detailed data on treatment were obtained on 64 patients in whom bone cancer developed after childhood cancer. As compared with 209 matched controls who had survived cancer in childhood but who did not have bone cancer later, patients who had had radiation therapy had a 2.7-fold risk (95 percent confidence interval, 1.0 to 7.7) and a sharp dose-response gradient reaching a 40-fold risk after doses to the bone of more than 6000 rad. The relative dose-response effect among patients who had been treated for retinoblastoma resembled that among patients with all other types of initial tumors, although the cumulative risk of bone cancer in the retinoblastoma group was higher. Similar numbers of patients were treated with orthovoltage and megavoltage; the patterns of risk among categories of doses did not differ according to the type of voltage. After adjustment for radiation therapy, treatment with alkylating agents was also linked to bone cancer (relative risk, 4.7; 95 percent confidence interval, 1.0 to 22.3), with the risk increasing as cumulative drug exposure rose. We conclude that both radiotherapy and chemotherapy with alkylating agents for childhood cancer increase the subsequent risk of bone cancer.

Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort

Objectives To assess the incidence of and risks for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities among adult survivors of childhood and adolescent cancers. Design Retrospective cohort study. Setting 26 institutions that participated in the Childhood Cancer Survivor Study. Participants 14 358 five year survivors of cancer diagnosed under the age of 21 with leukaemia, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer between 1970 and 1986. Comparison group included 3899 siblings of cancer survivors. Main outcome measures Participants or their parents (in participants aged less than 18 years) completed a questionnaire collecting information on demographic characteristics, height, weight, health habits, medical conditions, and surgical procedures occurring since diagnosis. The main outcome measures were the incidence of and risk factors for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities in survivors of cancer compared with siblings. Results Survivors of cancer were significantly more likely than siblings to report congestive heart failure (hazard ratio (HR) 5.9, 95% confidence interval 3.4 to 9.6; P<0.001), myocardial infarction (HR 5.0, 95% CI 2.3 to 10.4; P<0.001), pericardial disease (HR 6.3, 95% CI 3.3 to 11.9; P<0.001), or valvular abnormalities (HR 4.8, 95% CI 3.0 to 7.6; P<0.001). Exposure to 250 mg/m2 or more of anthracyclines increased the relative hazard of congestive heart failure, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. Cardiac radiation exposure of 1500 centigray or more increased the relative hazard of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by twofold to sixfold compared to non-irradiated survivors. The cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis. Conclusion Survivors of childhood and adolescent cancer are at substantial risk for cardiovascular disease. Healthcare professionals must be aware of these risks when caring for this growing population.

Cancer Incidence After Retinoblastoma: Radiation Dose and Sarcoma Risk

CONTEXT There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. OBJECTIVE To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development. DESIGN Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. SETTING/PARTICIPANTS A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. RESULTS Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05). CONCLUSIONS Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.

Second Malignant Neoplasms Among Long-Term Survivors of Hodgkin’s Disease: A Population-Based Evaluation Over 25 Years

PURPOSE To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkins disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment. PATIENTS AND METHODS Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed. RESULTS Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377; O/E = 2.9), digestive tract (Obs = 376; O/E = 1.7), and female breast (Obs = 234; O/E = 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 51 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect. CONCLUSION Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested.

Leukemia Following Hodgkin's Disease

To investigate the effect of different treatments for Hodgkins disease on the risk of leukemia, we used an international collaborative group of cancer registries and hospitals to perform a case-control study of 163 cases of leukemia following treatment for Hodgkins disease. For each case patient with leukemia, three matched controls were chosen who had been treated for Hodgkins disease but in whom leukemia did not develop. The use of chemotherapy alone to treat Hodgkins disease was associated with a relative risk of leukemia of 9.0 (95 percent confidence interval, 4.1 to 20) as compared with the use of radiotherapy alone. Patients treated with both had a relative risk of 7.7 (95 percent confidence interval, 3.9 to 15). After treatment with more than six cycles of combinations including procarbazine and mechlorethamine, the risk of leukemia was 14-fold higher than after radiotherapy alone. The use of radiotherapy in combination with chemotherapy did not increase the risk of leukemia above that produced by the use of chemotherapy alone, but there was a dose-related increase in the risk of leukemia in patients who received radiotherapy alone. The peak in the risk of leukemia came about five years after chemotherapy began, and a large excess persisted for at least eight years after it ended. After adjusting for drug regimen, we found that patients who had undergone splenectomy had at least double the risk of leukemia of patients who had not, and an advanced stage of Hodgkins disease carried a somewhat higher risk of leukemia than Stage I disease. We conclude that chemotherapy for Hodgkins disease greatly increases the risk of leukemia and that this increased risk appears to be dose-related and unaffected by concomitant radiotherapy. In addition, the risk is greater for patients with more advanced stages of Hodgkins disease and for those who undergo splenectomy.

Breast cancer mortality after diagnostic radiography : Findings from the U.S. Scoliosis Cohort Study

Study Design. A retrospective cohort study was conducted in 5573 female patients with scoliosis who were referred for treatment at 14 orthopedic medical centers in the United States. Patients were less than 20 years of age at diagnosis which occurred between 1912 and 1965. Objectives. To evaluate patterns in breast cancer mortality among women with scoliosis, with special emphasis on risk associated with diagnostic radiograph exposures. Summary of Background Data. A pilot study of 1030 women with scoliosis revealed a nearly twofold statistically significant increased risk for incident breast cancer. Although based on only 11 cases, findings were consistent with radiation as a causative factor. Methods. Medical records were reviewed for information on personal characteristics and scoliosis history. Diagnostic radiograph exposures were tabulated based on review of radiographs, radiology reports in the medical records, radiograph jackets, and radiology log books. Radiation doses were estimated for individual examinations. The mortality rate of the cohort through January 1, 1997, was determined by using state and national vital statistics records and was compared with that of women in the general U. S. population. Results. Nearly 138,000 radiographic examinations were recorded. The average number of examinations per patient was 24.7 (range, 0–618); mean estimated cumulative radiation dose to the breast was 10.8 cGy (range, 0–170). After excluding patients with missing information, 5466 patients were included in breast cancer mortality analyses. Their mean age at diagnosis was 10.6 years and average length of follow-up was 40.1 years. There were 77 breast cancer deaths observed compared with the 45.6 deaths expected on the basis of U.S. mortality rates (standardized mortality ratio [SMR] = 1.69; 95% confidence interval [CI] = 1.3–2.1). Risk increased significantly with increasing number of radiograph exposures and with cumulative radiation dose. The unadjusted excess relative risk per Gy was 5.4 (95% CI = 1.2–14.1); when analyses were restricted to patients who had undergone at least one radiographic examination, the risk estimate was 2.7 (95% CI = −0.2–9.3). Conclusions. These data suggest that exposure to multiple diagnostic radiographic examinations during childhood and adolescence may increase the risk of breast cancer among women with scoliosis; however, potential confounding between radiation dose and severity of disease and thus with reproductive history may explain some of the increased risk observed.

The Childhood Cancer Survivor Study: A National Cancer Institute–Supported Resource for Outcome and Intervention Research

Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.

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.

Obesity in Adult Survivors of Childhood Acute Lymphoblastic Leukemia: A Report from the Childhood Cancer Survivor Study

PURPOSE To determine whether adult survivors (>or= 18 years of age) of childhood acute lymphoblastic leukemia (ALL) are at increased risk for obesity and to assess patient and treatment variables that influence risk. PATIENTS AND METHODS A retrospective cohort of participants of the Childhood Cancer Survivor Study was used to compare 1,765 adult survivors of childhood ALL to 2,565 adult siblings of childhood cancer survivors. Body-mass index (BMI; kilograms per square meter), calculated from self-reported heights and weights, was used to determine the prevalence of being overweight (BMI, 25-29.9) or obese (BMI >or= 30.0). Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for being overweight or obese among ALL survivors relative to the sibling control group. RESULTS The age- and race-adjusted OR for being obese in survivors treated with cranial radiation doses >or= 20 Gy in comparison with siblings was 2.59 for females (95% CI, 1.88 to 3.55; P <.001) and 1.86 for males (95% CI, 1.33 to 2.57; P <.001). The OR for obesity was greatest among females diagnosed at 0 to 4 years of age and treated with radiation doses >or= 20 Gy (OR, 3.81; 95% CI, 2.34 to 5.99; P <.001). Obesity was not associated with treatment consisting of chemotherapy only or with cranial radiation doses of 10 to 19 Gy. CONCLUSION Cranial radiotherapy >or= 20 Gy is associated with an increased prevalence of obesity, especially in females treated at a young age. It is imperative that healthcare professionals recognize this risk and develop strategies to enhance weight control and encourage longitudinal follow-up.