Susan A. Smith

Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study

BACKGROUND Survivors of malignant disease in childhood who have had radiotherapy to the head, neck, or upper thorax have an increased risk of subsequent primary thyroid cancer, but the magnitude of risk over the therapeutic dose range has not been well established. We aimed to quantify the long-term risk of thyroid cancer after radiotherapy and chemotherapy. METHODS In a nested case-control study, 69 cases with pathologically confirmed thyroid cancer and 265 matched controls without thyroid cancer were identified from 14,054 5-year survivors of cancer during childhood from the Childhood Cancer Survivor Study cohort. Childhood cancers were diagnosed between 1970 and 1986 with cohort follow-up to 2000. FINDINGS Risk of thyroid cancer increased with radiation doses up to 20-29 Gy (odds ratio 9.8 [95% CI 3.2-34.8]). At doses greater than 30 Gy, a fall in the dose-response relation was seen. Both the increased and decreased risks were more pronounced in those diagnosed with a first primary malignant disease before age 10 years than in those older than 10 years. Furthermore, the fall in risk remained when those diagnosed with Hodgkins lymphoma were excluded. Chemotherapy for the first cancer was not associated with thyroid-cancer risk, and it did not modify the effect of radiotherapy. 29 (42%) cases had a first diagnosis of Hodgkins lymphoma compared with 49 (19%) controls. 11 (42%) of those who had Hodgkins lymphoma had subsequent thyroid cancers smaller than 1 cm compared with six (17%) of those who had other types of childhood cancer (p=0.07). INTERPRETATION The reduction in radiation dose-response for risk of thyroid cancer after childhood exposure to thyroid doses higher than 30 Gy is consistent with a cell-killing effect. Standard long-term follow-up of patients who have had Hodgkins lymphoma for detection of thyroid cancer should also be undertaken for survivors of any cancer during childhood who received radiotherapy to the thorax or head and neck region.

Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study

PURPOSE The purpose of this study was to quantify the risk of breast cancer in relation to radiation dose and chemotherapy among survivors of childhood cancer. METHODS We conducted a case-control study of breast cancer in a cohort of 6,647 women who were 5-year survivors of childhood cancer and who were treated during 1970 through 1986. One hundred twenty patients with histologically confirmed breast cancer were identified and were individually matched to four selected controls on age at initial cancer and time since initial cancer. Medical physicists estimated radiation dose to the breast tumor site and ovaries on the basis of medical records. RESULTS The odds ratio for breast cancer increased linearly with radiation dose, and it reached 11-fold for local breast doses of approximately 40 Gy relative to no radiation (P for trend < .0001). Risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries (P = .002). The excess odds ratio per Gy was 0.36 for those who received ovarian doses less than 5 Gy and was 0.06 for those who received higher doses. Radiation-related risk did not vary significantly by age at exposure. Borderline significantly elevated risks were seen for doxorubicin, dactinomycin, dacarbazine, and carmustine. CONCLUSION Results confirm the radiation sensitivity of the breast in girls age 10 to 20 years but do not demonstrate a strong effect of age at exposure within this range. Irradiation of the ovaries at doses greater than 5 Gy seems to lessen the carcinogenic effects of breast irradiation, most likely by reducing exposure of radiation-damaged breast cells to stimulating effects of ovarian hormones.

Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study

Abstract Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose–response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8–31.5). At thyroid radiation doses >20 Gy, a downturn in the dose–response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P  =  0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.

Dose to the Contralateral Breast From Radiotherapy and Risk of Second Primary Breast Cancer in the WECARE Study

PURPOSE To quantify the risk of second primary breast cancer in the contralateral breast (CB) after radiotherapy (RT) for first breast cancer. METHODS AND MATERIALS The study population included participants in the Womens Environmental, Cancer, and Radiation Epidemiology study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were <55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using multivariable-adjusted conditional logistic regression models. RESULTS Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women <40 years of age who received >1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR = 2.5, 95% CI 1.4-4.5). No excess risk was observed in women >40 years of age. Women <40 years of age with follow-up periods >5 years had a RR of 3.0 (95% CI 1.1-8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI 0.1-3.0). CONCLUSIONS Women <40 years of age who received a radiation dose >1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.

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.

Second solid cancers after radiotherapy for breast cancer in SEER cancer registries

Background:Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites.Methods:We evaluated long-term second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields.Results:By the end of 2005 (median follow-up=13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI)=1.33–1.58) for high-dose second cancer sites (1+ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04–1.15) for contralateral breast cancer (≈1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5–0.99 Gy, RR=0.89 (0.74–1.06)) or low doses (<0.5 Gy, RR=1.01 (0.95–1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI=69–284) contralateral breast cancers or 5% (2–8%) of the total in all 1+year survivors, and 292 (222–362) other solid cancers or 6% (4–7%) of the total.Conclusions:Most second solid cancers in breast cancer survivors are not related to radiotherapy.

Study design: Evaluating gene–environment interactions in the etiology of breast cancer – the WECARE study

IntroductionDeficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.DesignTo examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.ConclusionsOur study design improves the potential for detecting gene–environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case–control sets and enhanced our ability to detect radiation–genotype interactions.

Thyroid Cancer in Childhood Cancer Survivors: A Detailed Evaluation of Radiation Dose Response and its Modifiers

Abstract Ronckers, C. M., Sigurdson, A. J., Stovall, M., Smith, S. A., Mertens, A. C., Liu, Y., Hammond, S., Land, C. E., Neglia, J. P., Donaldson, S. S., Meadows, A. T., Sklar, C. A., Robison, L. L. and Inskip, P. D. Thyroid Cancer in Childhood Cancer Survivors: A Detailed Evaluation of Radiation Dose Response and its Modifiers. Radiat. Res. 166, 618–628 (2006). Radiation exposure at a young age is a strong risk factor for thyroid cancer. We conducted a nested case-control study of 69 thyroid cancer cases and 265 controls from a cohort of 14,054 childhood cancer survivors to evaluate the shape of the radiation dose–response relationship, in particular at high doses, and to assess modification of the radiation effects by patient and treatment characteristics. We considered several types of statistical models to estimate the excess relative risk (ERR), mainly guided by radiobiological models. A two-parameter model with a term linear in dose and a negative exponential in dose squared provided the best parsimonious description with an ERR of 1.3 per gray (95% confidence interval 0.4–4.1) at doses below 6 Gy and a relative decrease in ERR of 0.2% per unit dose squared with increasing dose, that is, decreases in the ERR/Gy of 53% at 20 Gy and 95% at 40 Gy. Further analyses using spline models suggested that the significant nonlinearity at high doses was characterized most appropriately as a true downturn rather than a flattening of the dose–response curve. We found no statistically significant modification of the dose–response relationship by patient characteristics; however, the linear parameter (i.e., the ERR/ Gy at doses less than 6 Gy) did decrease consistently and linearly with increasing age at childhood cancer diagnosis, from 4.45 for 0–1-year-olds to 0.48 for 15–20-year-olds. In summary, we applied models derived from radiobiology to describe the radiation dose–response curve for thyroid cancer in an epidemiological study and found convincing evidence for a downturn in risk at high doses.

Breast Cancer After Chest Radiation Therapy for Childhood Cancer

PURPOSE The risk of breast cancer is high in women treated for a childhood cancer with chest irradiation. We sought to examine variations in risk resulting from irradiation field and radiation dose. PATIENTS AND METHODS We evaluated cumulative breast cancer risk in 1,230 female childhood cancer survivors treated with chest irradiation who were participants in the CCSS (Childhood Cancer Survivor Study). RESULTS Childhood cancer survivors treated with lower delivered doses of radiation (median, 14 Gy; range, 2 to 20 Gy) to a large volume (whole-lung field) had a high risk of breast cancer (standardized incidence ratio [SIR], 43.6; 95% CI, 27.2 to 70.3), as did survivors treated with high doses of delivered radiation (median, 40 Gy) to the mantle field (SIR, 24.2; 95% CI, 20.7 to 28.3). The cumulative incidence of breast cancer by age 50 years was 30% (95% CI, 25 to 34), with a 35% incidence among Hodgkin lymphoma survivors (95% CI, 29 to 40). Breast cancer-specific mortality at 5 and 10 years was 12% (95% CI, 8 to 18) and 19% (95% CI, 13 to 25), respectively. CONCLUSION Among women treated for childhood cancer with chest radiation therapy, those treated with whole-lung irradiation have a greater risk of breast cancer than previously recognized, demonstrating the importance of radiation volume. Importantly, mortality associated with breast cancer after childhood cancer is substantial.

Tissue doses from radiotherapy of cancer of the uterine cervix

For use in an epidemiologic study of subsequent tumors, absorbed doses from brachytherapy and external beam radiotherapy were measured and calculated for various tissues of patients treated for cancer of the uterine cervix. External beams included orthovoltage x rays (1.9 and 3.0 mm Cu half-value layer), cobalt-60 gamma rays, 2 MV x rays, and 25 MV X rays. The brachytherapy sources were encapsulated radium. Measurements were made in an Alderson anthropomorphic phantom and a water phantom; calculations were made using a Monte Carlo technique or standard radiotherapy methods. Depending upon stage of disease and radiation energy, the absorbed doses (cGy) from typical treatment regimes to tissues of interest were: ovaries, 1400-5200; stomach, 130-320; kidneys, 120-310; pancreas, 100-260; lungs 22-48; breasts, 19-52; thyroid, 6-17; salivary glands, 4-11; brain, 2-7, and total active bone marrow, 320-1100. The lower values of each range were for stage I of the disease.