Benzene exposure and risk of benzene poisoning in Chinese workers.

OBJECTIVES: Benzene is a known haematoxin and leukemogen that can cause benzene poisoning (BP), that is, a persistent reduction in white cell counts that is strongly associated with increased risk of lymphohaematopoietic malignancies. Data are needed on the exposure-response, particularly at low doses and susceptible populations for clinical and regulatory purposes. METHODS: In a case-cohort study among 110 631 Chinese workers first employed 1949-1987 and followed up during 1972-1999, we evaluated BP risk according to benzene exposure level and investigated risk modification by subject (sex, attained age) and exposure-related factors (latency, exposure windows, age at first benzene exposure, coexposure to toluene) using excess relative risk and excess absolute risk models. RESULTS: There were 538 BP cases and 909 benzene-exposed referents. The exposure metric with best model fit was cumulative benzene exposure during a 5-year risk window, followed by a 9-month lag period before BP diagnosis. Estimated excess absolute risk of BP at age 60 increased from 0.5% for subjects in the lowest benzene exposure category (>0 to 10 ppm-years) to 5.0% for those in the highest category (>100 ppm-years) compared with unexposed subjects. Increased risks were apparent at low cumulative exposure levels and for workers who were first exposed at <30 years of age. CONCLUSIONS: Our data show a clear association between benzene exposure and BP, beginning at low cumulative benzene exposure levels with no threshold, and with higher risks for workers exposed at younger ages. These findings are important because BP has been linked to a strongly increased development of lymphohaematopoietic malignancies.

Issues in Interpreting Epidemiologic Studies of Populations Exposed to Low-Dose, High-Energy Photon Radiation.

This article addresses issues relevant to interpreting findings from 26 epidemiologic studies of persons exposed to low-dose radiation. We review the extensive data from both epidemiologic studies of persons exposed at moderate or high doses and from radiobiology that together have firmly established radiation as carcinogenic. We then discuss the use of the linear relative risk model that has been used to describe data from both low- and moderate- or high-dose studies. We consider the effects of dose measurement errors; these can reduce statistical power and lead to underestimation of risks but are very unlikely to bring about a spurious dose response. We estimate statistical power for the low-dose studies under the assumption that true risks of radiation-related cancers are those expected from studies of Japanese atomic bomb survivors. Finally, we discuss the interpretation of confidence intervals and statistical tests and the applicability of the Bradford Hill principles for a causal relationship.

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Summary Bias Assessment and Meta-Analysis.

BACKGROUND: Ionizing radiation is an established carcinogen, but risks from low-dose exposures are controversial. Since the Biological Effects of Ionizing Radiation VII review of the epidemiological data in 2006, many subsequent publications have reported excess cancer risks from low-dose exposures. Our aim was to systematically review these studies to assess the magnitude of the risk and whether the positive findings could be explained by biases. METHODS: Eligible studies had mean cumulative doses of less than 100 mGy, individualized dose estimates, risk estimates, and confidence intervals (CI) for the dose-response and were published in 2006-2017. We summarized the evidence for bias (dose error, confounding, outcome ascertainment) and its likely direction for each study. We tested whether the median excess relative risk (ERR) per unit dose equals zero and assessed the impact of excluding positive studies with potential bias away from the null. We performed a meta-analysis to quantify the ERR and assess consistency across studies for all solid cancers and leukemia. RESULTS: Of the 26 eligible studies, 8 concerned environmental, 4 medical, and 14 occupational exposure. For solid cancers, 16 of 22 studies reported positive ERRs per unit dose, and we rejected the hypothesis that the median ERR equals zero (P = .03). After exclusion of 4 positive studies with potential positive bias, 12 of 18 studies reported positive ERRs per unit dose (P = .12). For leukemia, 17 of 20 studies were positive, and we rejected the hypothesis that the median ERR per unit dose equals zero (P = .001), also after exclusion of 5 positive studies with potential positive bias (P = .02). For adulthood exposure, the meta-ERR at 100 mGy was 0.029 (95% CI = 0.011 to 0.047) for solid cancers and 0.16 (95% CI = 0.07 to 0.25) for leukemia. For childhood exposure, the meta-ERR at 100 mGy for leukemia was 2.84 (95% CI = 0.37 to 5.32); there were only two eligible studies of all solid cancers. CONCLUSIONS: Our systematic assessments in this monograph showed that these new epidemiological studies are characterized by several limitations, but only a few positive studies were potentially biased away from the null. After exclusion of these studies, the majority of studies still reported positive risk estimates. We therefore conclude that these new epidemiological studies directly support excess cancer risks from low-dose ionizing radiation. Furthermore, the magnitude of the cancer risks from these low-dose radiation exposures was statistically compatible with the radiation dose-related cancer risks of the atomic bomb survivors.

Dose-volume effects of breast cancer radiation therapy on the risk of second oesophageal cancer.

PURPOSE: To investigate the relationship between oesophagus dose-volume distribution and long-term risk of oesophageal cancer after radiation therapy for breast cancer. MATERIALS AND METHODS: In a case-control study nested within a cohort of 289,748 ≥5-year survivors of female breast cancer treated in 1943-2003 in five countries, doses to the second primary cancer (DSPC) and individual dose-volume histograms (DVH) to the entire oesophagus were reconstructed for 252 oesophageal cancer cases and 488 matched controls (median follow-up time: 13, range: 5-37 years). Using conditional logistic regression, we estimated excess odds ratios (EOR) of oesophageal cancer associated with DVH metrics. We also investigated whether DVH metrics confounded or modified DSPC-related -risk estimates. RESULTS: Among the DVH metrics evaluated, median dose (Dmedian) to the entire oesophagus had the best statistical performance for estimating risk of all histological types combined (EOR/Gy = 0.071, 95% confidence interval [CI]: 0.018 to 0.206). For squamous cell carcinoma, the most common subtype, the EOR/Gy for Dmedian increased by 31% (95% CI: 3% to 205%) for each increment of 10% of V30 (p = 0.02). Adjusting for DVH metrics did not materially change the EOR/Gy for DSPC, but there was a borderline significant positive interaction between DSPC and V30 (p = 0.07). CONCLUSION: This first study investigating the relationship between oesophagus dose-volume distribution and oesophageal cancer risk showed an increased risk per Gy for Dmedian with larger volumes irradiated at high doses. While current techniques allows better oesophagus sparing, constraints applied to Dmedian and V30 could potentially further reduce the risk of oesophageal cancer.

Lung cancer mortality associated with protracted low-dose occupational radiation exposures and smoking behaviors in U.S. radiologic technologists, 1983-2012.

In the Japanese atomic bomb survivors, risk of lung cancer has been shown to increase with greater acute exposure to ionizing radiation. Although similar findings have been observed in populations exposed to low-dose, protracted radiation, such studies lack information on cigarette smoking history, a potential confounder. In a cohort of 106 068 U.S. radiologic technologists, we examined the association between estimated cumulative lung absorbed dose from occupational radiation exposure and lung cancer mortality. Poisson regression models, adjusted for attained age, sex, birth cohort, pack-years smoked and years since quitting smoking, were used to calculate linear excess relative risks (ERR) per 100 mGy, using time-dependent cumulative lung absorbed dose, lagged 10 years. Mean cumulative absorbed dose to the lung was 25 mGy (range: 0-810 mGy). During the 1983 to 2012 follow-up, 1090 participants died from lung cancer. Greater occupational radiation lung dose was not associated with lung cancer mortality overall (ERR per 100 mGy: -0.02, 95% CI: <0-0.13). However, significant dose-response relationships were observed for some subgroups, which might be false-positive results given the number of statistical tests performed. As observed in other studies of radiation and smoking, the interaction between radiation and smoking appeared to be sub-multiplicative with an ERR per 100 mGy of 0.41 (95% CI: 0.01-1.15) for those who smoked <20 pack-years and -0.03 (95% CI: <0-0.15) for those who smoked ≥20 pack-years. Our study provides some evidence that greater protracted radiation exposure in the low-dose range is positively associated with lung cancer mortality.

Benzene exposure-response and risk of lymphoid neoplasms in Chinese workers: A multicenter case-cohort study.

BACKGROUND: While international agreement supports a causal relationship of benzene exposure with acute myeloid leukemia, there is debate about benzene and lymphoid neoplasm risks. METHODS: In a case-cohort study with follow-up of 110 631 Chinese workers during 1972-1999, we evaluated benzene exposure-response for non-Hodgkin lymphoma (NHL), lymphoid leukemias (LL), acute lymphocytic leukemia (ALL), and total lymphoid neoplasms (LN). We estimated benzene exposures using state-of-the-art hierarchical modeling of occupational factors calibrated with historical routine measurements and evaluated cumulative exposure-response using Cox regression. RESULTS: NHL and other specified LN were increased in exposed vs unexposed workers. However, there was no evidence of exposure-response for NHL or other specified LN. Based on a linear exposure-response, relative risks at 100 parts per million-years (RR at 100 ppm-years) for cumulative benzene exposure using a 2-year lag (exposure at least 2 years before the time at risk) were 1.05 for NHL (95 percent confidence interval (CI) = 0.97, 1.27; 32 cases), 1.11 for LL (95% CI < 0, 1.66; 12 cases), 1.21 for ALL (95% CI < 0, 3.53; 10 cases), and 1.02 for total LN (95% CI < 0, 1.16; 49 cases). No statistically significant exposure-response trends were apparent for these LN for 2 to <10-year or ≥10-year lags. NHL risks were not significantly modified by sex, age, or year at first exposure, attained age, or time since exposure. CONCLUSION: Given the study strengths and limitations, we found little evidence of exposure-response for benzene and NHL, LL, ALL, or total LN, although NHL and other specified LN were increased in exposed vs unexposed individuals.

Bone and Soft-Tissue Sarcoma Risk in Long-Term Survivors of Hereditary Retinoblastoma Treated With Radiation.

PURPOSE: Survivors of hereditary retinoblastoma have excellent survival but substantially increased risks of subsequent bone and soft-tissue sarcomas, particularly after radiotherapy. Comprehensive investigation of sarcoma risk patterns would inform clinical surveillance for survivors. PATIENTS AND METHODS: In a cohort of 952 irradiated survivors of hereditary retinoblastoma who were originally diagnosed during 1914 to 2006, we quantified sarcoma risk with standardized incidence ratios (SIRs) and cumulative incidence analyses. We conducted analyses separately for bone and soft-tissue sarcomas occurring in the head and neck (in/near the radiotherapy field) versus body and extremities (out of field). RESULTS: Of 105 bone and 124 soft-tissue sarcomas, more than one half occurred in the head and neck (bone, 53.3%; soft tissue, 51.6%), one quarter in the body and extremities (bone, 29.5%; soft tissue, 25.0%), and approximately one fifth in unknown/unspecified locations (bone, 17.1%; soft tissue, 23.4%). We noted substantially higher risks compared with the general population for head and neck versus body and extremity tumors for both bone (SIR, 2,213; 95% CI, 1,671 to 2,873 v SIR, 169; 95% CI, 115 to 239) and soft-tissue sarcomas (SIR, 542; 95% CI, 418 to 692 v SIR, 45.7; 95% CI, 31.1 to 64.9). Head and neck bone and soft-tissue sarcomas were diagnosed beginning in early childhood and continued well into adulthood, reaching a 60-year cumulative incidence of 6.8% (95% CI, 5.0% to 8.7%) and 9.3% (95% CI, 7.0% to 11.7%), respectively. In contrast, body and extremity bone sarcoma incidence flattened after adolescence (3.5%; 95% CI, 2.3% to 4.8%), whereas body and extremity soft-tissue sarcoma incidence was rare until age 30, when incidence rose steeply (60-year cumulative incidence, 6.6%; 95% CI, 4.1% to 9.2%), particularly for females (9.4%; 95% CI, 5.1% to 13.8%). CONCLUSION: Strikingly elevated bone and soft-tissue sarcoma risks differ by age, location, and sex, highlighting important contributions of both radiotherapy and genetic susceptibility. These data provide guidance for the development of a risk-based screening protocol that focuses on the highest sarcoma risks by age, location, and sex.

Cataract risk in US radiologic technologists assisting with fluoroscopically guided interventional procedures: a retrospective cohort study.

OBJECTIVES: To assess radiation exposure-related work history and risk of cataract and cataract surgery among radiologic technologists assisting with fluoroscopically guided interventional procedures (FGIP). METHODS: This retrospective study included 35 751 radiologic technologists who reported being cataract-free at baseline (1994-1998) and completed a follow-up questionnaire (2013-2014). Frequencies of assisting with 21 types of FGIP and use of radiation protection equipment during five time periods (before 1970, 1970-1979, 1980-1989, 1990-1999, 2000-2009) were derived from an additional self-administered questionnaire in 2013-2014. Multivariable-adjusted relative risks (RRs) for self-reported cataract diagnosis and cataract surgery were estimated according to FGIP work history. RESULTS: During follow-up, 9372 technologists reported incident physician-diagnosed cataract; 4278 of incident cases reported undergoing cataract surgery. Technologists who ever assisted with FGIP had increased risk for cataract compared with those who never assisted with FGIP (RR: 1.18, 95% CI 1.11 to 1.25). Risk increased with increasing cumulative number of FGIP; the RR for technologists who assisted with >5000 FGIP compared with those who never assisted was 1.38 (95% CI 1.24 to 1.53; p trend <0.001). These associations were more pronounced for FGIP when technologists were located ≤3 feet (≤0.9 m) from the patient compared with >3 feet (>0.9 m) (RRs for >5000 at ≤3 feet vs never FGIP were 1.48, 95% CI 1.27 to 1.74 and 1.15, 95% CI 0.98 to 1.35, respectively; pdifference=0.04). Similar risks, although not statistically significant, were observed for cataract surgery. CONCLUSION: Technologists who reported assisting with FGIP, particularly high-volume FGIP within 3 feet of the patient, had increased risk of incident cataract. Additional investigation should evaluate estimated dose response and medically validated cataract type.

Benzene Exposure Response and Risk of Myeloid Neoplasms in Chinese Workers: A Multicenter Case-Cohort Study.

BACKGROUND: There is international consensus that benzene exposure is causally related to acute myeloid leukemia (AML), and more recent evidence of association with myelodysplastic syndromes (MDS). However, there are uncertainties about the exposure response, particularly risks by time since exposure and age at exposure. METHODS: In a case-cohort study in 110 631 Chinese workers followed up during 1972-1999 we evaluated combined MDS/AML (n = 44) and chronic myeloid leukemia (n = 18). We estimated benzene exposures using hierarchical modeling of occupational factors calibrated with historical routine measurements, and evaluated exposure response for cumulative exposure and average intensity using Cox regression; P values were two-sided. RESULTS: Increased MDS/AML risk with increasing cumulative exposure in our a priori defined time window (2 to <10 years) before the time at risk was suggested (Ptrend = 08). For first exposure (within the 2 to <10-year window) before age 30 years, the exposure response was stronger (P = .004) with rate ratios of 1.12 (95% confidence interval [CI] = 0.27 to 4.29), 5.58 (95% CI = 1.65 to 19.68), and 4.50 (95% CI = 1.22 to 16.68) for cumulative exposures of more than 0 to less than 40, 40 to less than 100, and at least 100 ppm-years, respectively, compared with no exposure. There was little evidence of exposure response after at least 10 years (Ptrend = .94), regardless of age at first exposure. Average intensity results were generally similar. The risk for chronic myeloid leukemia was increased in exposed vs unexposed workers, but appeared to increase and then decrease with increasing exposure. CONCLUSION: For myeloid neoplasms, the strongest effects were apparent for MDS/AML arising within 10 years of benzene exposure and for first exposure in the 2 to less than 10-year window before age 30 years.

Risk of subsequent myeloid neoplasms after radiotherapy treatment for a solid cancer among adults in the United States, 2000-2014.

Although increased risk of acute myeloid leukemia (AML) has been observed after chemotherapy and radiotherapy, less is known about radiotherapy-related risks of specific AML subtypes and other specific myeloid neoplasms. We used the US population-based cancer registry data to evaluate risk of myeloid neoplasms among three cohorts of cancer survivors initially treated with radiotherapy only. We included 1-year survivors of first primary thyroid (radioiodine only, stages I-IV; N = 49 879), prostate (excluding stage IV; N = 237 439), or uterine corpus cancers (stage I-II; N = 16 208) diagnosed during 2000-2013. We calculated standardized incidence ratios (SIRs) and excess absolute risks (EARs). Thyroid cancer survivors had significantly elevated risks of total AML (SIR = 2.77, 95% CI: 1.99-3.76), AML with cytogenetic abnormalities (SIR = 3.90, 95% CI: 1.57-8.04), AML with myelodysplasia-related changes (SIR = 2.87, 95% CI: 1.05-6.25), and BCR-ABL1-positive chronic myelogenous leukemia (CML) (SIR = 5.38, 95% CI: 2.58-9.89). Irradiated prostate and uterine corpus cancer survivors were at elevated risk for total AML (SIR = 1.14, 95% CI: 1.03-1.27 and SIR = 1.77, 95% CI: 1.01-2.87, respectively), AML with cytogenetic abnormalities (SIR = 2.52, 95% CI: 1.84-3.37 and SIR = 7.21, 95% CI: 2.34-16.83, respectively), and acute promyelocytic leukemia (SIR = 3.20, 95% CI: 2.20-4.49 and SIR = 8.88, 95% CI: 2.42-22.73, respectively). In addition, prostate cancer survivors were at increased risk of BCR-ABL1-positive CML (SIR = 2.11, 95% CI: 1.52-2.85). Our findings support the importance of diagnostic precision in myeloid neoplasm classification since susceptibility following radiotherapy may vary by myeloid neoplasm subtype, thereby informing risk/benefit discussions in first primary cancer treatment.

Mortality in U.S. Physicians Likely to Perform Fluoroscopy-guided Interventional Procedures Compared with Psychiatrists, 1979 to 2008.

Purpose To compare total and cause-specific mortality rates between physicians likely to have performed fluoroscopy-guided interventional (FGI) procedures (referred to as FGI MDs) and psychiatrists to determine if any differences are consistent with known radiation risks. Materials and Methods Mortality risks were compared in nationwide cohorts of 45 634 FGI MDs and 64 401 psychiatrists. Cause of death was ascertained from the National Death Index. Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for FGI MDs versus psychiatrists, with adjustment (via stratification) for year of birth and attained age. Results During follow-up (1979-2008), 3506 FGI MDs (86 women) and 7814 psychiatrists (507 women) died. Compared with psychiatrists, FGI MDs had lower total (men: RR, 0.80 [95% CI: 0.77, 0.83]; women: RR, 0.80 [95% CI: 0.63, 1.00]) and cancer (men: RR, 0.92 [95% CI: 0.85, 0.99]; women: RR, 0.83 [95% CI: 0.58, 1.18]) mortality. Mortality because of specific types of cancer, total and specific types of circulatory diseases, and other causes were not elevated in FGI MDs compared with psychiatrists. On the basis of small numbers, leukemia mortality was elevated among male FGI MDs who graduated from medical school before 1940 (RR, 3.86; 95% CI: 1.21, 12.3). Conclusion Overall, total deaths and deaths from specific causes were not elevated in FGI MDs compared with psychiatrists. These findings require confirmation in large cohort studies with individual doses, detailed work histories, and extended follow-up of the subjects to substantially older median age at exit. © RSNA, 2017 Online supplemental material is available for this article.

Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects.

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Increased pancreatic cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear. METHODS: Among 23 982 5-year TC survivors diagnosed during 1947-1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs). RESULTS: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated with a 2.9-fold (95% confidence interval (CI) 1.0-7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trend<0.001), with an OR of 4.6 (95% CI 1.9-11.0) for ⩾25 Gy vs <25 Gy. Radiation-related risks remained elevated ⩾20 years after TC diagnosis (P=0.020). The risk increased with the number of cycles of chemotherapy with alkylating or platinum agents (P=0.057), although only one case was exposed to platinum. CONCLUSIONS: A dose-response relationship exists between radiation to the pancreas and subsequent cancer risk, and persists for over 20 years. These excesses, although small, should be considered when radiotherapy with exposure to the pancreas is considered for newly diagnosed patients. Additional data are needed on the role of chemotherapy.

A retrospective cohort study of cause-specific mortality and incidence of hematopoietic malignancies in Chinese benzene-exposed workers.

Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI = 1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI = 1.2, 2.3) and diseases of blood forming organs (RR = ∞, 95% CI = 3.4, ∞). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95%CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95%CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders.

Second malignant neoplasms and cardiovascular disease following radiotherapy.

Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (i.e., radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (i.e., dose-response relationships). Major conclusions of the NCRP include: (1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and (2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include (1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; (2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; (3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; (4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and (5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.

Stomach cancer risk after treatment for hodgkin lymphoma.

PURPOSE: Treatment-related stomach cancer is an important cause of morbidity and mortality among the growing number of Hodgkin lymphoma (HL) survivors, but risks associated with specific HL treatments are unclear. PATIENTS AND METHODS: We conducted an international case-control study of stomach cancer nested in a cohort of 19,882 HL survivors diagnosed from 1953 to 2003, including 89 cases and 190 matched controls. For each patient, we quantified cumulative doses of specific alkylating agents (AAs) and reconstructed radiation dose to the stomach tumor location. RESULTS: Stomach cancer risk increased with increasing radiation dose to the stomach (Ptrend < .001) and with increasing number of AA-containing chemotherapy cycles (Ptrend = .02). Patients who received both radiation to the stomach ≥ 25 Gy and high-dose procarbazine (≥ 5,600 mg/m(2)) had strikingly elevated stomach cancer risk (25 cases, two controls; odds ratio [OR], 77.5; 95% CI, 14.7 to 1452) compared with those who received radiation < 25 Gy and procarbazine < 5,600 mg/m(2) (Pinteraction < .001). Risk was also elevated (OR, 2.8; 95% CI, 1.3 to 6.4) among patients who received radiation to the stomach ≥ 25 Gy but procarbazine < 5,600 mg/m(2); however, no procarbazine-related risk was evident with radiation < 25 Gy. Treatment with dacarbazine also increased stomach cancer risk (12 cases, nine controls; OR, 8.8; 95% CI, 2.1 to 46.6), after adjustment for radiation and procarbazine doses. CONCLUSION: Patients with HL who received subdiaphragmatic radiotherapy had dose-dependent increased risk of stomach cancer, with marked risks for patients who also received chemotherapy containing high-dose procarbazine. For current patients, risks and benefits of exposure to both procarbazine and subdiaphragmatic radiotherapy should be weighed carefully. For patients treated previously, GI symptoms should be evaluated promptly.

Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008.

Therapy-related acute myeloid leukemia (tAML) is a rare but highly fatal complication of cytotoxic chemotherapy. Despite major changes in cancer treatment, data describing tAML risks over time are sparse. Among 426068 adults initially treated with chemotherapy for first primary malignancy (9 US population-based cancer registries, 1975-2008), we identified 801 tAML cases, 4.70 times more than expected in the general population (P < .001). Over time, tAML risks increased after chemotherapy for non-Hodgkin lymphoma (n = 158; Poisson regression Ptrend < .001), declined for ovarian cancer (n = 72; Ptrend < .001), myeloma (n = 62; Ptrend = .02), and possibly lung cancer (n = 65; Ptrend = .18), and were significantly heterogeneous for breast cancer (n = 223; Phomogeneity = .005) and Hodgkin lymphoma (n = 58; Phomogeneity = .007). tAML risks varied significantly by age at first cancer and latency and were nonsignificantly heightened with radiotherapy for lung, breast, and ovarian cancers. We identified newly emerging elevated tAML risks in patients treated with chemotherapy since 2000 for esophageal, cervical, prostate, and possibly anal cancers; and since the 1990s for bone/joint and endometrial cancers. Using long-term, population-based data, we observed significant variation in tAML risk with time, consistent with changing treatment practices and differential leukemogenicity of specific therapies. tAML risks should be weighed against the benefits of chemotherapy, particularly for new agents and new indications for standard agents.

Risk of salivary gland cancer after childhood cancer: a report from the Childhood Cancer Survivor Study.

PURPOSE: To evaluate effects of radiation therapy, chemotherapy, cigarette smoking, and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS). METHODS AND MATERIALS: Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology, and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking, and alcohol consumption. RESULTS: During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR = 39.4; 95% CI = 25.4-57.8). The EAR was 9.8 per 100,000 person-years. Risk increased linearly with radiation dose (excess relative risk = 0.36/Gy; 95% CI = 0.06-2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking, or alcohol intake. CONCLUSION: Although the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least 2 decades after exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.

Second malignant neoplasms and cardiovascular disease following radiotherapy.

Second malignant neoplasms (SMNs) and cardiovascular disease (CVD) are among the most serious and life-threatening late adverse effects experienced by the growing number of cancer survivors worldwide and are due in part to radiotherapy. The National Council on Radiation Protection and Measurements (NCRP) convened an expert scientific committee to critically and comprehensively review associations between radiotherapy and SMNs and CVD, taking into account radiobiology; genomics; treatment (ie, radiotherapy with or without chemotherapy and other therapies); type of radiation; and quantitative considerations (ie, dose-response relationships). Major conclusions of the NCRP include: 1) the relevance of older technologies for current risk assessment when organ-specific absorbed dose and the appropriate relative biological effectiveness are taken into account and 2) the identification of critical research needs with regard to newer radiation modalities, dose-response relationships, and genetic susceptibility. Recommendation for research priorities and infrastructural requirements include 1) long-term large-scale follow-up of extant cancer survivors and prospectively treated patients to characterize risks of SMNs and CVD in terms of radiation dose and type; 2) biological sample collection to integrate epidemiological studies with molecular and genetic evaluations; 3) investigation of interactions between radiotherapy and other potential confounding factors, such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility; 4) focusing on adolescent and young adult cancer survivors, given the sparse research in this population; and 5) construction of comprehensive risk prediction models for SMNs and CVD to permit the development of follow-up guidelines and prevention and intervention strategies.