Lois B. Travis

Solid Cancers after Bone Marrow Transplantation

BACKGROUND The late effects of bone marrow transplantation, including cancer, need to be determined in a large population at risk. METHODS We studied 19,229 patients who received allogeneic transplants (97.2 percent) or syngeneic transplants (2.8 percent) between 1964 and 1992 at 235 centers to evaluate the risk of the development of a new solid cancer. Risk factors relating to the patient, the transplant, and the course after transplantation were evaluated. RESULTS The transplant recipients were at significantly higher risk of new solid cancers than the general population (observed cases, 80; ratio of observed to expected cases, 2.7; P<0.001). The risk was 8.3 times higher than expected among those who survived 10 or more years after transplantation. The cumulative incidence rate was 2.2 percent (95 percent confidence interval, 1.5 to 3.0 percent) at 10 years and 6.7 percent (95 percent confidence interval, 3.7 to 9.6 percent) at 15 years. The risk was significantly elevated (P<0.05) for malignant melanoma (ratio of observed to expected cases, 5.0) and cancers of the buccal cavity (11.1), liver (7.5), brain or other parts of the central nervous system (7.6), thyroid (6.6), bone (13.4), and connective tissue (8.0). The risk was higher for recipients who were younger at the time of transplantation than for those who were older (P for trend <0.001). In multivariate analyses, higher doses of total-body irradiation were associated with a higher risk of solid cancers. Chronic graft-versus-host disease and male sex were strongly linked with an excess risk of squamous-cell cancers of the buccal cavity and skin. CONCLUSIONS Patients undergoing bone marrow transplantation have an increased risk of new solid cancers later in life. The trend toward an increased risk over time after transplantation and the greater risk among younger patients indicate the need for life-long surveillance.

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.

New Malignant Diseases After Allogeneic Marrow Transplantation for Childhood Acute Leukemia

PURPOSE To determine the incidence of and risk factors for second malignancies after allogeneic bone marrow transplantation (BMT) for childhood leukemia. PATIENTS AND METHODS We studied a cohort of 3, 182 children diagnosed with acute leukemia before the age of 17 years who received allogeneic BMT between 1964 and 1992 at 235 centers. Observed second cancers were compared with expected cancers in an age- and sex-matched general population. Risks factors were evaluated using Poisson regression. RESULTS Twenty-five solid tumors and 20 posttransplant lymphoproliferative disorders (PTLDs) were observed compared with 1.0 case expected (P <.001). Cumulative risk of solid cancers increased sharply to 11.0% (95% confidence interval, 2.3% to 19.8%) at 15 years and was highest among children at ages younger than 5 years at transplantation. Thyroid and brain cancers (n = 14) accounted for most of the strong age trend; many of these patients received cranial irradiation before BMT. Multivariate analyses showed increased solid tumor risks associated with high-dose total-body irradiation (relative risk [RR] = 3.1) and younger age at transplantation (RR = 3.7), whereas chronic graft-versus-host disease was associated with a decreased risk (RR = 0.2). Risk factors for PTLD included chronic graft-versus-host disease (RR = 6.5), unrelated or HLA-disparate related donor (RR = 7. 5), T-cell-depleted graft (RR = 4.8), and antithymocyte globulin therapy (RR = 3.1). CONCLUSION Long-term survivors of BMT for childhood leukemia have an increased risk of solid cancers and PTLDs, related to both transplant therapy and treatment given before BMT. Transplant recipients, especially those given radiation, should be monitored closely for second cancers.

Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978–2001: An analysis of 26,758 cases

Soft tissue sarcomas (STS) are a heterogeneous group of uncommon tumors that show a broad range of differentiation that may reflect etiologic distinction. Routine tabulations of STS are not morphology‐specific. Further, the lack of inclusion of sarcomas arising in all organs in most standard evaluations underestimates the true rates. We analyzed the 1978–2001 Surveillance, Epidemiology and End Results program incidence rates of STS regardless of primary site, except bones and joints, using the 2002 criteria of the WHO classification. There were 26,758 cases available for analysis. Leiomyosarcomas accounted for 23.9%, malignant fibrous histiocytomas 17.1%, liposarcomas 11.5%, dermatofibrosarcomas 10.5%, rhabdomyosarcomas 4.6% and angiosarcomas 4.1%. Almost half (47.9%) of the sarcomas arose in the soft tissues, 14.0% in the skin and 7.0% in the uterus. Overall, incidence rates were highest among black women (6.26/100,000 woman‐years) and the lowest among white women (4.60/100,000). Age‐adjusted rates increased at 1.2% and 0.8% per year among white males and females, respectively, both trends statistically significant, while rates among blacks declined slightly. About 40% of leiomyosarcomas among women were uterine in origin, with a black/white rate ratio of 1.7. This rate ratio increased to 2.0 when we accounted for the lower prevalence of intact uteri among black compared to white women. Total STS rates rose exponentially with age. Rates for both uterine leiomyosarcoma and dermatofibrosarcoma increased rapidly during the childbearing years, peaking at about age 40 and 50, respectively. Incidence patterns of STS varied markedly by histologic type, supporting the notion that these tumors may be etiologically distinct.

Risk of Leukemia after Platinum-Based Chemotherapy for Ovarian Cancer

BACKGROUND Platinum-based chemotherapy is the cornerstone of modern treatment for ovarian, testicular, and other cancers, but few investigations have quantified the late sequelae of such treatment. METHODS We conducted a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had received a diagnosis of invasive ovarian cancer between 1980 and 1993. Leukemia developed after the administration of platinum-based therapy in 96 women. These women were matched to 272 control patients. The type, cumulative dose, and duration of chemotherapy and the dose of radiation delivered to active bone marrow were compared in the two groups. RESULTS Among the women who received platinum-based combination chemotherapy for ovarian cancer, the relative risk of leukemia was 4.0 (95 percent confidence interval, 1.4 to 11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5 (95 percent confidence interval, 1.2 to 36.6) and 3.3 (95 percent confidence interval, 1.1 to 9.4), respectively. We found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (P for trend <0.001). Radiotherapy without chemotherapy (median dose, 18.4 Gy) did not increase the risk of leukemia. CONCLUSIONS Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. Nevertheless, the substantial benefit that platinum-based treatment offers patients with advanced disease outweighs the relatively small excess risk of leukemia.

Mechanisms of therapy-related carcinogenesis

Therapy-related cancers, defined as second primary cancers that arise as a consequence of chemotherapy and/or radiotherapy, are unusual in that they have a well-defined aetiology. Knowledge of the specific nature of the initiating exposure and exactly when it occurred has made it easier to identify crucial genetic events and to model these in vitro and in vivo. As such, the study of therapy-related cancers has led to the elucidation of discrete mechanisms of carcinogenesis, including DNA double-strand-break-induced gene translocation and genomic instability conferred by loss of DNA repair. Unsurprisingly, some of these mechanisms seem to operate in the development of sporadic cancers.

The epidemiology of second primary cancers.

Background: Due to improvements in early detection, supportive care, and treatment, the number of cancer survivors in the United States has tripled since 1971 and is growing by 2% each year. In 2001, there were ∼10 million cancer survivors, representing 3.5% of the population. As survival after a diagnosis of cancer improves, quantification of the late effects of cancer and its therapy become critical. One of the most serious events experienced by cancer survivors is the diagnosis of a new cancer. Second- or higher-order cancers now account for ∼16% of incident cancers reported to the National Cancer Institutes Surveillance, Epidemiology, and End Results Program. Subsequent neoplasms may not necessarily be attributable to prior cancer treatment but may also reflect the effect of shared etiologic factors, environmental exposures, host characteristics, and combinations of influences, including gene-environment and gene-gene interactions. Methods/Results: This review will focus on selected highlights and recent findings in treatment-associated malignancies, with an emphasis on survivors of adult cancer. Current study methods will also be summarized. Conclusions: Important opportunities for future research include the prospective identification of patient subgroups that might be at heightened susceptibility of developing therapy-associated second cancers to modify planned treatments or select alternative management strategies. For the burgeoning population of cancer survivors treated successfully with past regimens, including those therapies that have been subsequently refined, continued quantification of late effects, including second cancers, remains highly relevant in terms of raising clinician and patient awareness, for informed counseling, and for the development of risk-adapted long-term management strategies. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2020–6)

Dose Reconstruction for Therapeutic and Diagnostic Radiation Exposures: Use in Epidemiological Studies

Abstract Stovall, M., Weathers, R., Kasper, C., Smith, S. A., Travis, L., Ron, E. and Kleinerman, R. Dose Reconstruction for Therapeutic and Diagnostic Radiation Exposures: Use in Epidemiological Studies. Radiat. Res. 166, 141–157 (2006). This paper describes methods developed specifically for reconstructing individual organ- and tissue-absorbed dose of radiation from past exposures from medical treatments and procedures for use in epidemiological studies. These methods have evolved over the past three decades and have been applied to a variety of medical exposures including external-beam radiation therapy and brachytherapy for malignant and benign diseases as well as diagnostic examinations. The methods used for estimating absorbed dose to organs in and outside the defined treatment volume generally require archival data collection, abstraction and review, and phantom measurements to simulate past exposure conditions. Three techniques are used to estimate doses from radiation therapy: (1) calculation in three-dimensional mathematical computer models using an extensive database of out-of-beam doses measured in tissue-equivalent materials, (2) measurement in anthropomorphic phantoms constructed of tissue-equivalent material, and (3) calculation using a three-dimensional treatment-planning computer. For diagnostic exposures, doses are estimated from published data and software based on Monte Carlo techniques. We describe and compare these methods of dose estimation and discuss uncertainties in estimated organ doses and potential for future improvement. Seven epidemiological studies are discussed to illustrate the methods.

Mast Cell Leukemia: Report of a Case and Review of the Literature

We report the clinical and pathologic findings in one case of mast cell leukemia observed in a series of 60 patients with systemic mast cell disease. The leukemic variant of systemic mast cell disease is rapidly fatal (mean duration of survival, less than 6 months) in contrast to most nonleukemic cases, which follow an indolent clinical course. On the basis of our case and eight previously reported cases, mast cell leukemia is characterized by a substantial increase in atypical mast cells in the peripheral blood, diffuse infiltration with atypical mast cells in the bone marrow, a strong association with peptic ulcer disease, prominent constitutional symptoms, and hepatosplenomegaly. These cases should be distinguished from malignant mastocytosis without a substantial number of circulating atypical mast cells and also cases of acute nonlymphocytic leukemia that arise in the background of systemic mast cell disease.

A cohort study of cancer among benzene-exposed workers in China: Overall results

A large cohort study of 74,828 benzene-exposed and 35,805 unexposed workers employed between 1972 and 1987 in 12 cities in China were followed to determine mortality from all causes and the incidence of lymphohematopoietic malignancies and other hematologic disorders. Benzene-exposed study subjects were employed in a variety of occupations, including painting, printing, and the manufacture of footwear, paint, and other chemicals. All-cause mortality was similar in the benzene-exposed and unexposed comparison group. Statistically significant excess deaths were noted among benzene-exposed subjects for leukemia (RR = 2.3, 95% CP 1.1-5.0), malignant lymphoma (RR = 4.5, 95% CI: 1.3-28.4), and nonneoplastic diseases of the blood (RR = 95% CP 2.5-infinity), and a marginally significant excess was noted for lung cancer (RR = 1.4, 95% CI: 1.0-2.0). Risk was significantly elevated for the incidence of all lymphohematopoietic malignancies (RR = 2.6, 95% CI: 1.5-5.0), malignant lymphoma (RR = 3.5, 95% CI: 1.2-14.9), and leukemia (RR = 2.6, 95% CI.. 1.3-5.7). Among the leukemia subtypes, only acute myelogenous leukemia (AML) incidence was significantly elevated (RR = 3.1, 95% CI: 1.2-10.7), although nonsignificant excesses were also noted for chronic myelogenous leukemia (CML) (RR = 2.6, 95% CI: 0.7-16.9) and lymphocytic leukemias (RR = 2.8, 95% CI.. 0.5-54.5). Significant excesses were found for aplastic anemia (RR = infinity, 95% CI: 2.2-co) and myelodysplastic syndrome (RR = infinity, 95% CI: 1.7-infinity). Employment in benzene-associated occupations in China is associated with a wide spectrum of myelogenous and lymphocytic malignant diseases and related disorders. Investigations continue to assess the nature of these associations.