Radiation dose and leukemia risk in patients treated for cancer of the cervix

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.     

Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries

The numbers of second cancers among 182,040 women treated for cervical cancer that were reported to 15 cancer registries in 8 countries were compared to the numbers expected had the same risk prevailed as in the general population. A small 9% excess of second cancers (5,146 observed vs. 4,736 expected) occurred 1 or more years after treatment. Large radiation doses experienced by 82,616 women did not dramatically alter their risk of developing a second cancer; at most, about 162 of 3,324 second cancers (approximately equal to 5%) could be attributed to radiation. The relative risk (RR = 1.1) for developing cancer in organs close to the cervix that had received high radiation exposures--most notably, the bladder, rectum, uterine corpus, ovary, small intestine, bone, and connective tissue--and for developing multiple myeloma increased with time since treatment. No similar increase was seen for 99,424 women not treated with radiation. Only a slight excess of acute and non-lymphocytic leukemia was found among irradiated women (RR = 1.3), and substantially fewer cases were observed than expected on the basis of current radiation risk estimates. The small risk of leukemia may be associated with low doses of radiation absorbed by the bone marrow outside the pelvis, inasmuch as the marrow in the pelvis may have been destroyed or rendered inactive by very large radiotherapy exposures. There was little evidence of a radiation effect for cancers of the stomach, colon, liver, and gallbladder, for melanoma and other skin cancers, or for chronic lymphocytic leukemia despite substantial exposures. An excess of thyroid cancer possibly was related to the low dose received by this organ. Ovarian damage caused by radiation may have been responsible for a low breast cancer risk (RR = 0.7), which was evident even among postmenopausal women. A substantial excess of lung cancer (RR = 3.7) largely may be due to misclassification of metastases and the confounding influence of cigarette smoking. Women who were under 30 or over 50 years of age when irradiated were at greatest absolute risk for developing a second cancer. The RR, however, was higher among those under age 30 years at exposure (RR = 3.9) than among older women. The expression period for radiation-induced solid tumors appeared to continue to the end of life.     

Treatment-associated leukemia following testicular cancer

BACKGROUND: Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of leukemia following radiotherapy and chemotherapy for testicular cancer. METHODS: Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case-control study of leukemia was undertaken. Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided. RESULTS: Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend =.02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend =.001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5-8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks. CONCLUSIONS: Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose-response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.     

Radiation dose and breast cancer risk in patients treated for cancer of the cervix

The relationship between breast cancer and radiation treatment for cervical cancer was evaluated in an international study of 953 women who subsequently developed breast cancer and 1,806 matched controls. Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed for exposed subjects on the basis of their original radiotherapy records. Overall, 88% of the breast cancer cases and 89% of the controls received radiation treatment [relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.7-1.2]. Among women with intact ovaries (561 cases, 1,037 controls), radiotherapy was linked to a significant 35% reduction in breast cancer risk, attributable in all likelihood to the cessation of ovarian function. Ovarian doses of 6 Gy were sufficient to reduce breast cancer risk but larger doses did not reduce risk further. This saturation-type response is probably due to the killing of a critical number of ovarian cells. Cervical cancer patients without ovaries (145 cases, 284 controls) were analyzed separately because such women are at especially low natural risk for breast cancer development. In theory, any effect of low-dose breast exposure, received incidentally during treatment for cervical cancer, should be more readily detectable. Among women without ovaries, there was a slight increase in breast cancer risk (RR = 1.07; 95% CI = 0.6-2.0), and a suggestion of a dose response with the RR being 1.0, 0.7, 1.5 and 3.1 for breast doses of 0, 0.01-0.24, 0.25-0.49 and 0.50+ Gy, respectively. However, this trend of increasing RR was not statistically significant. If low-dose radiation increases the risk of breast cancer among women over age 40 years, it appears that the risk is much lower than would be predicted from studies of younger women exposed to higher doses.     

Adjuvant radiotherapy and risk of contralateral breast cancer.

BACKGROUND: The risk of contralateral breast cancer is increased twofold to fivefold for breast cancer patients. A registry-based cohort study in Denmark suggested that radiation treatment of the first breast cancer might increase the risk for contralateral breast cancer among 10-year survivors. PURPOSE: Our goal was to assess the role of radiation in the development of contralateral breast cancer. METHODS: A nested case-control study was conducted in a cohort of 56,540 women in Denmark diagnosed with invasive breast cancer from 1943 through 1978. Case patients were 529 women who developed contralateral breast cancer 8 or more years after first diagnosis. Controls were women with breast cancer who did not develop contralateral breast cancer. One control was matched to each case patient on the basis of age, calendar year of initial breast cancer diagnosis, and survival time. Radiation dose to the contralateral breast was estimated for each patient on the basis of radiation measurements and abstracted treatment information. The anatomical position of each breast cancer was also abstracted from medical records. RESULTS: Radiotherapy had been administered to 82.4% of case patients and controls, and the mean radiation dose to the contralateral breast was estimated to be 2.51 Gy. Radiotherapy did not increase the overall risk of contralateral breast cancer (relative risk = 1.04; 95% confidence interval = 0.74-1.46), and there was no evidence that risk varied with radiation dose, time since exposure, or age at exposure. The second tumors in case patients were evenly distributed in the medial, lateral, and central portions of the breast, a finding that argues against a causal role of radiotherapy in tumorigenesis. CONCLUSIONS: The majority of women in our series were perimenopausal or postmenopausal (53% total versus 38% premenopausal and 9% of unknown status) and received radiotherapy at an age when the breast tissue appears least susceptible to the carcinogenic effects of radiation. Based on a dose of 2.51 Gy and estimates of radiation risk from other studies, a relative risk of only 1.18 would have been expected for a population of women exposed at an average age of 51 years. Thus, our data provide additional evidence that there is little if any risk of radiation-induced breast cancer associated with exposure of breast tissue to low-dose radiation (e.g., from mammographic x rays or adjuvant radiotherapy) in later life.     

Ionizing radiation and tobacco use increases the risk of a subsequent lung carcinoma in women with breast cancer: case-only design.

PURPOSE: To analyze the risk of lung cancer in women treated with radiotherapy for breast cancer. We accessed the lung dose in relation to different radiotherapy techniques, provided the excess relative risk (ERR) estimate for radiation-associated lung cancer, and evaluated the influence of tobacco use. PATIENTS AND METHODS: The Swedish Cancer Registry was used to identify 182 women diagnosed with breast and subsequent lung cancers in Stockholm County during 1958 to 2000. Radiotherapy was administered to 116 patients. Radiation dose was estimated from the original treatment charts, and information on smoking history was searched for in case records and among relatives. The risk of lung cancer was assessed in a case-only approach, where each woman contributed a pair of lungs. RESULTS: The average mean lung dose to the ipsilateral lung was 17.2 Gy (range, 7.1 to 32.0 Gy). A significantly increased relative risk (RR) of a subsequent ipsilateral lung cancer was observed at > or = 10 years of follow-up (RR = 2.04; 95% CI, 1.24 to 3.36). Squamous cell carcinoma (RR = 4.00; 95% CI, 1.50 to 10.66) was the histopathologic subgroup most closely related to ionizing radiation. The effect of radiotherapy was restricted to smokers only (RR = 3.08; 95% CI, 1.61 to 5.91). The ERR/Gy for women with latency > or = 10 years after exposure was 0.11 (95% CI, 0.02 to 0.44). CONCLUSION: Radiotherapy for breast cancer significantly increases the risk of lung carcinoma more than 10 years after exposure in women who smoked at time of breast cancer.     

Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment.

PURPOSE: To assess long-term site-specific risks of second malignancy after Hodgkin's disease in relation to age at treatment and other factors. PATIENTS AND METHODS: A cohort of 5,519 British patients with Hodgkin's disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS: Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION: Age at treatment has a major effect on risk of second malignancy after Hodgkin's disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed-modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkin's disease require detailed investigation.     

Cancer among medical diagnostic x-ray workers in China

Cancer incidence among 27,011 diagnostic x-ray workers was compared to that of 25,782 other medical specialists employed between 1950 and 1980 in China. X-ray workers had a 50% higher risk of developing cancer than the other specialists [relative risk (RR) = 1.5; 95% CI = 1.3-1.7]. Leukemia was strongly linked to radiation work (RR = 3.5, n = 30). Cancers of the breast (RR = 1.4, n = 11), thyroid (RR = 2.1, n = 7), and skin (RR = 1.5, n = 6) were increased among x-ray workers employed for 10 or more years. High risks of cancers of the esophagus (RR = 3.5, n = 15) and liver (RR = 2.4, n = 48) were not consistent with a radiation effect since risk did not vary by duration of employment. This finding suggested that some differences might exist between groups of hospital workers in social class, alcohol intake, dietary habits, and other risk factors. No excess lung cancer (RR = 0.9, n = 22) or multiple myeloma (n = 0) was observed. Significant excesses of leukemia and cancers of the breast and thyroid occurred among x-ray workers first employed prior to 1960 when radiation exposures in China were high. In fact, it was not uncommon for employees to be given time off from x-ray work because their wbc count was severely depressed. These data indicated that repeated exposure to x-rays over many years can increase the risk of leukemia and several other tumors but apparently not that of lung cancer.     

Is family history of breast cancer a marker of susceptibility to exposures in the incidence of de novo adult acute leukemia?

The risk factors for adult acute leukemia incidence have been difficult to establish.Family history of cancer might interact with environmental exposures to produce associations that are otherwise difficult to detect. In addition to family history of leukemia or other hematopoietic cancers, family history of breast cancer could be a marker of susceptibility, because leukemia and breast cancer are known to cluster in families that have specific germ-line mutations. In a population-based case control study of 779 incident adult acute leukemia patients and 625 controls, we estimated the relative risk for exposed individuals with a family history compared with unexposed individuals without a family history (RR(11)), along with a measure of interdependence, the interaction contrast ratio. Combined with a family history of breast cancer, ever-smoking [RR(11) = 2.4, 95% confidence interval (CI): 1.2-4.8], general solvent exposure (RR(11) = 1.9, 95% CI: 1.1-3.4), aromatic hydrocarbon exposure (RR(11) = 3.8, 95% CI: 1.1-14), and diagnostic ionizing radiation exposure (RR(11) = 2.1, 95% CI: 1.2-3.8) were all associated with increased incidence. Furthermore, there was no increased incidence associated with any of these exposures in the absence of a family history of breast cancer and no increased incidence for family history of breast cancer in the absence of exposures. The pattern of relative risks strongly suggested synergy across exposures. Family history of breast cancer might be a marker of susceptibility to a range of leukemia risk factors, whose effects are generally weak or nonexistent when considered alone.     

Cancer incidence among medical diagnostic X-ray workers in China, 1950 to 1985

A second follow-up of 27,011 diagnostic X-ray workers in China revealed a 21% greater incidence of cancer than expected based on the experience of 25,782 physicians who did not routinely use X-rays (RR = 1.21; 95% Cl: 1.08 to 1.35). This risk is lower than the 50% excess reported previously and reflects, in part, the reduced risk among workers first employed after 1965, when hospital exposures to radiation probably were lower than in earlier years. The X-ray workers were employed between 1950 and 1985 and followed for an average of 16.1 years. Significantly elevated risks were seen for leukemia (RR = 2.4, n = 34 cases), and cancers of the esophagus (RR = 5.2, n = 19), liver (RR = 1.8, n = 65), and skin (RR = 2.8, n = 9). Cancers of the breast (RR = 1.5, n = 20), thyroid (RR = 1.7, n = 8), and bone (RR = 7.6, n = 4) also occurred more often than expected. Non-significant deficits were observed for cancers of the oral cavity and pharynx (RR = 0.6, n = 16), colon and rectum (RR = 0.8, n = 20), stomach (RR = 0.8, n = 36), and lung (RR = 0.9, n = 45). Excess risks for leukemia and esophageal cancer were seen among men but not among women. The RR for leukemia was higher for X-ray workers who began employment before 1970 than for those who started more recently and also for those who were young when employment began. The patterns of risk associated with duration of work, and with age and calendar time of initial employment, suggest that the excesses of leukemia and skin cancer, and, possibly, cancers of the breast and thyroid, were due to occupational exposure to X-rays. However, there was little evidence that radiation contributed to the increased occurrences of liver or esophageal cancers.     

Breast cancer in women with scoliosis exposed to multiple diagnostic x rays

Although exposure to ionizing radiation is a recognized risk factor for breast cancer, the potential hazard from low-dose, fractionated exposures during early breast development has not been thoroughly evaluated. Women with scoliosis represent a valuable population for studying this issue because they are exposed to multiple diagnostic x rays during childhood and adolescence, times when the breast may be highly sensitive to the carcinogenic effects of radiation. A study was conducted of 1,030 women with scoliosis who were seen at four Minneapolis area medical facilities between 1935 and 1965. The average age at diagnosis was 12.3 years; 60% of the women had idiopathic scoliosis. Individual x-ray films were counted and the number per patient ranged from 0 to 618 films (mean, 41.5). On average, the x-ray exposures were given over an 8.7-year period. Ninety percent of the women were located, of whom over 92% responded to a mail questionnaire or telephone interview. The average period of observation was 26 years. Overall, 11 cases of breast cancer were reported, compared with six expected (standardized incidence ratio = 1.82, 90% confidence interval = 1.0-3.0). Excess risk increased with time since exposure and was highest among those followed for more than 30 years (standardized incidence ratio = 2.4). Risk also increased with the number of x rays and with the estimated radiation dose to the breast (mean, 13 rad). These data suggest that frequent exposure to low-level diagnostic radiation during childhood or adolescence may increase the risk of breast cancer.     

Increased incidence of stroke in women with breast cancer

Meta-analyses have shown an excess of vascular deaths in women with breast cancer given radiotherapy (RT). In women with breast cancer, RT to the supraclavicular lymph nodes gives a substantial radiation dose to the proximal carotid artery. RT is known to increase the risk of carotid stenosis and ischaemic stroke in head and neck cancer. A study base of 25,171 women with breast cancer was defined. A linkage between the study base and the Hospital Discharge Register yielded 1766 women who were diagnosed with a stroke after a breast cancer. The observed number of strokes was compared with the expected number in the background population. The Relative Risk (RR) of stroke in the study group with breast cancer was 1.12 (95% Confidence Interval (CI)=1.07-1.17). The increased risk was confined to the subtype cerebral infarction, RR=1.12 (95% CI=1.05-1.19). A statistically significant increase in the risk of stroke was seen among women with a history of breast cancer. Whether this risk is associated with the breast cancer disease per se or related to any treatment requires further study.     

Cancer mortality in a radiation-exposed cohort of Massachusetts tuberculosis patients

The mortality experience of 13,385 tuberculosis patients treated between 1925 and 1954 in Massachusetts was determined through August 1986. Among 6,285 patients examined by X-ray fluoroscopy an average of 77 times during lung collapse therapy and followed for up to 50 yr (average = 25 yr), no increase in the total number of cancer deaths occurred [standardized mortality ratio (SMR) = 1.05, n = 424]. In contrast, the 7,100 patients treated by other means were at significant risk of dying from cancer (SMR = 1.3), especially of sites linked to cigarette smoking and alcohol use. Among the irradiated patients, estimates of mean radiation doses to the breast, lung, esophagus, and active bone marrow were 0.75, 0.84, 0.80, and 0.09 Gy, respectively. Cancers of the breast (SMR = 1.4, n = 62) and esophagus (SMR = 2.1, n = 14) were significantly increased. The risk of esophageal cancer, however, decreased with time since exposure. Lung cancer (SMR = 0.8, n = 69) and leukemia (SMR = 1.2, n = 17) were not elevated. Despite a wide range of doses to the lung, reaching over 8 Gy, there was no evidence of a dose response. Lung cancer risk also did not vary by time since exposure or age at exposure. Adjustment for smoking and the amount of lung tissue at risk did not appreciably modify these findings. These data suggest that frequent exposures to low doses of radiation over a period of several years increase the occurrence of cancer of the breast. When compared with studies of atomic bomb survivors, however, the fractionated exposures experienced by this cohort appear less effective in causing lung cancer than single exposures of the same total dose.     

Risk of leukemia associated with the first course of cancer treatment: an analysis of the Surveillance, Epidemiology, and End Results Program experience

The risk of leukemia associated with the first course of cancer treatment was evaluated in over 440,000 patients diagnosed during 1973-80 (average follow-up = 1.91 yr) from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Although the reporting of the first course of therapy probably was incomplete, 34 acute nonlymphocytic leukemias (ANLL) developed compared with 7.6 expected among 70,674 patients known to receive initial chemotherapy [relative risk (RR) = 4.5, 95% confidence interval (Cl) = 3.1-6.3]. Significant ANLL excesses were observed following chemotherapy for breast cancer (RR = 8.1), ovarian cancer (RR = 22.2), and multiple myeloma (RR = 9.5). Patients initially treated with radiation (with no record of chemotherapy) also had a significantly increased ANLL risk; 45 leukemias occurred versus 17.9 expected (RR = 2.5, 95% Cl = 1.8-3.4). In this group, excess ANLL were found following irradiation for uterine corpus cancer (RR = 4.0). Kidney and renal pelvis cancer patients had a twofold leukemia risk (all types) that was unrelated to treatment (RR = 2.2).     

Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease

BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.     

Risk of subsequent cancer following a primary CNS tumor

Improvements in survival among central nervous system (CNS) tumor patients has made the risk of developing a subsequent cancer an important survivorship issue. Such a risk is likely influenced by histological and treatment differences between CNS tumors. De-identified data for 41,159 patients with a primary CNS tumor diagnosis from 9 Surveillance, Epidemiology and End Results (SEER) registries were used to calculate potential risk for subsequent cancer development. Relative risk (RR) and 95 % confidence interval (CI) of subsequent cancer was calculated using SEER*Stat 7.0.9, comparing observed number of subsequent cancers versus expected in the general United States population. For all CNS tumors studied, there were 830 subsequent cancers with a RR of 1.26 (95 % CI, 1.18–1.35). Subsequent cancers were observed in the CNS, digestive system, bones/joints, soft tissue, thyroid and leukemia. Radiotherapy was associated with an elevated risk, particularly in patients diagnosed with a medulloblastoma/primitive neuroectodermal tumor (MPNET). MPNET patients who received radiotherapy were at a significant risk for development of cancers of the digestive system, leukemia, bone/joint and cranial nerves. Glioblastoma multiforme patients who received radiotherapy were at lower risks for female breast and prostate cancers, though at an elevated risk for cancers of the thyroid and brain. Radiotherapy is associated with subsequent cancer development, particularly for sites within the field of radiation, though host susceptibility and post-treatment status underlie this risk. Variation in subsequent cancer risk among different CNS tumor histological subtypes indicate a complex interplay between risk factors in subsequent cancer development.     

Cancer incidence after radiotherapy for skin hemangioma: a retrospective cohort study in Sweden

The cancer incidence was studied in 18,030 patients (33% males, 67% females) with skin hemangioma who were admitted to Radiumhemmet, Karolinska Hospital, Stockholm, Sweden, 1920-1959. Radium-226 sources were used in 12,821 patients, x-ray therapy was used in 2,515 patients, and no radiotherapy was given to 2,694 patients. Cancer incidence in the cohort was searched by record linkage with the Swedish Cancer Register for the period 1958-1982. The median age was 6 months for the treated patients and 8 months for the patients not receiving radiotherapy. In the group treated with radium-226 or orthovoltage x rays (greater than or equal to 100-kV peak), 224 cancers were observed [relative risk (RR) = 1.18; 95% confidence interval (CI) = 1.03-1.35]. In patients given contact x rays, 10 cancers were observed (RR = 0.71; 95% CI = 0.34-1.30). In patients not treated with ionizing radiation, 34 cancers were observed (RR = 0.93; 95% CI = 0.64-1.29). In patients treated with radium-226 or orthovoltage x rays, an RR of 1.65 was observed for breast cancer (95% CI = 1.26-2.13) and an RR of 2.73 was found for soft tissue tumors (95% CI = 1.18-5.38). Patients with brain tumors, thyroid cancers, and bone tumors had received radiotherapy close to the tumor site more often than expected. For patients with breast cancer, no such difference was found. For cancers of the breast and thyroid, the RR was higher in patients given more than one treatment.     

A meta-analysis on dose–response relationship between night shift work and the risk of breast cancer

This study aimed to conduct a systematic review to sum up evidence of the associations between different aspects of night shift work and female breast cancer using a dose–response meta-analysis approach.We systematicly searched all cohort and case–control studies published in English on MEDLINE, Embase, PSYCInfo, APC Journal Club and Global Health, from January 1971 to May 2013. We extracted effect measures (relative risk, RR; odd ratio, OR; or hazard ratio, HR) from individual studies to generate pooled results using meta-analysis approaches. A log-linear dose–response regression model was used to evaluate the relationship between various indicators of exposure to night shift work and breast cancer risk. Downs and Black scale was applied to assess the methodological quality of included studies.Ten studies were included in the meta-analysis. A pooled adjusted relative risk for the association between ‘ever exposed to night shift work’ and breast cancer was 1.19 [95% confidence interval (CI) 1.05–1.35]. Further meta-analyses on dose–response relationship showed that every 5-year increase of exposure to night shift work would correspondingly enhance the risk of breast cancer of the female by 3% (pooled RR = 1.03, 95% CI 1.01–1.05; P_{heterogeneity} < 0.001). Our meta-analysis also suggested that an increase in 500-night shifts would result in a 13% (RR = 1.13, 95% CI 1.07–1.21; P_{heterogeneity} = 0.06) increase in breast cancer risk.This systematic review updated the evidence that a positive dose–response relationship is likely to present for breast cancer with increasing years of employment and cumulative shifts involved in the work.     

Leukemia after therapy with alkylating agents for childhood cancer

The risk of leukemia was evaluated in 9,170 2-or-more-year survivors of childhood cancer in the 13 institutions of the Late Effects Study Group. Secondary leukemia occurred in 22 nonreferred individuals compared to 1.52 expected, based on general population rates [relative risk (RR) = 14; 95% confidence interval (CI), 9-22]. The influence of therapy for the first cancer on subsequent leukemia risk was determined by a case-control study conducted on 25 cases and 90 matched controls. Treatment with alkylating agents was associated with a significantly elevated risk of leukemia (RR = 4.8; 95% CI, 1.2-18.9). A strong dose-response relationship was also observed between leukemia risk and total dose of alkylating agents, estimated by an alkylator score. The RR of leukemia reached 23 in the highest dose category. Radiation therapy, however, did not increase risk. Although doxorubicin was also identified as a possible risk factor, the excess risk of leukemia following treatment for childhood cancer appears almost entirely due to alkylating agents.     

Leukemia in patients following radiotherapy for malignant neoplasms in the pelvic region

A prospective study of 1572 women treated with radiotherapy for cervical (1478 women) and ovarian cancer (94 women) was done. Patients had been followed clinically and especially by blood tests between 1961 and 1981, comprising 8990 woman-years (WY). Following radiotherapy, 5 patients developed non-lymphocytic leukemia [2 acute myeloblastic leukemia (AML), 1 acute monocytic leukemia (AMoL), and 2 chronic myeloid leukemia (CML)]. Based on rates for the general population, 0.45 case would be expected and, therefore, the relative risk was 11.2. The average mean marrow dose for all our subjects was calculated to be 1177 rad, the risk of radiation-induced leukemia was 0.43 excess case per year per one million women exposed to 1 rad of radiation to the bone marrow. Four patients with cervical cancer who developed leukemia were in a high-dose-rate group treated with both a linear accelerator (Linac) and remote afterloading system (RALS), and 1 patient with ovarian cancer who developed leukemia was treated with a Linac alone. This is the first report of a statistically significant increased risk of leukemia for patients treated with large doses of radiation for malignant neoplasms in the pelvic region.