Radiation Dose-Volume-Response Relationships for Adverse Events in Childhood Cancer Survivors: Introduction to the Scientific Issues in PENTEC.

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue-related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon-constituting approximately 1% of new incident cancers in the United States-and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography-based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC.

Risk and prognosis of secondary lung cancer after radiation therapy for thoracic malignancies.

OBJECTIVE: Radiation therapy (RT) may increase the risk of second cancer. This study aimed to determine the association between exposure to radiotherapy for the treatment of thoracic cancer (TC) and subsequent secondary lung cancer (SLC). MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (from 1975 to 2015) was queried for TC. Univariate Cox regression analyses and multiple primary standardized incidence ratios (SIRs) were used to assess the risk of SLC. Subgroup analyses of patients stratified by latency time since TC diagnosis, age at TC diagnosis, and calendar year of TC diagnosis stage were also performed. Overall survival and SLC-related death were compared among the RT and no radiation therapy (NRT) groups by using Kaplan-Meier analysis and competitive risk analysis. RESULTS: In a total of 329 129 observations, 147 847 of whom had been treated with RT. And 6799 patients developed SLC. Receiving radiotherapy was related to a higher risk of developing SLC for TC patients (adjusted HR, 1.25; 95% CI, 1.19-1.32; P < 0.001). The cumulative incidence of developing SLC in TC patients with RT (3.8%) was higher than the cumulative incidence (2.9%) in TC patients with NRT(P). The incidence risk of SLC in TC patients who received radiotherapy was significantly higher than the US general population (SIR, 1.19; 95% CI, 1.14-1.23; P < 0.050). CONCLUSIONS: Radiotherapy for TC was associated with higher risks of developing SLC compared with patients unexposed to radiotherapy.

Skin cancers are the most frequent cancers in fair-skinned populations, but we can prevent them.

Cancers of the skin are the most commonly occurring cancers in humans. In fair-skinned populations, up to 95% of keratinocyte skin cancers and 70-95% of cutaneous melanomas are caused by ultraviolet radiation and are thus theoretically preventable. Currently, however, there is no comprehensive global advice on practical steps to be taken to reduce the toll of skin cancer. To address this gap, an expert working group comprising clinicians and researchers from Africa, America, Asia, Australia, and Europe, together with learned societies (European Association of Dermato-Oncology, Euromelanoma, Euroskin, European Union of Medical Specialists, and the Melanoma World Society) reviewed the extant evidence and issued the following evidence-based recommendations for photoprotection as a strategy to prevent skin cancer. Fair skinned people, especially children, should minimise their exposure to ultraviolet radiation, and are advised to use protective measures when the UV index is forecast to reach 3 or higher. Protective measures include a combination of seeking shade, physical protection (e.g. clothing, hat, sunglasses), and applying broad-spectrum, SPF 30 + sunscreens to uncovered skin. Intentional exposure to solar ultraviolet radiation for the purpose of sunbathing and tanning is considered an unhealthy behaviour and should be avoided. Similarly, use of solaria and other artificial sources of ultraviolet radiation to encourage tanning should be strongly discouraged, through regulation if necessary. Primary prevention of skin cancer has a positive return on investment. We encourage policymakers to communicate these messages to the general public and promote their wider implementation.

Carcinogenic risk in patients treated with UVA-1 phototherapy: A 5-year retrospective study.

BACKGROUND: UVA-1 phototherapy was first used to treat atopic dermatitis and afterwards to several other skin diseases. The contribution of UVA-1 in human photocarcinogenesis, skin photoaging, immune suppression, and hyperpigmentation is now well established. The actual contribution of UVA-1 radiation to the development of malignant melanoma (MM) in humans cannot be excluded. PURPOSE: The aim of the study is to evaluate the risk of developing skin cancers (non-melanoma skin cancers (NMSCs) and MM) in patients treated with UVA-1 phototherapy with a 5-year dermatological follow-up. METHODS: We conducted a retrospective cohort study with 31 patients with morphea and atopic dermatitis treated with medium dose UVA-1 phototherapy (34 J/cm2). All enrolled patients underwent an oncologic prevention visit annually with a 5-year follow-up with clinical evaluation of the entire skin surface. RESULTS: During the 5-year follow-up, we recorded a case of basal cell carcinoma (BCC) in the cervical region and one case of MM on the back (pT1a). In both cases, the patients were female and affected by morphea. The Glogau 3 group is prevalent (42%), which is consistent with moderate to severe aging; the data appear to be compatible with the age. CONCLUSIONS: This study attests that medium-dose UVA-1 phototherapy does not increase the risk of developing skin tumors and that UVA-1 phototherapy is not a worsening factor of facial photoaging. The main limitation of the study is the small sample size, avoiding to obtain statistically significant values. It was not possible to analyze individually the actual daily sun exposure during the 5-year observation period and to correlate it in terms of time and tumor development. Further studies with large sample sizes will be needed to confirm our data. Our study reaffirms how the dermatological examination performed annually is essential in the follow-up of patients undergoing this type of therapy.

Extended analysis of solid cancer incidence among nuclear industry workers in the UK 1955-2011: comparison of workers first hired in earlier and later periods.

To address points arising from the recent study of nuclear workers in the USA and the International Nuclear Workers Study (INWORKS), concerning the difference in solid cancer risk estimates between those first hired in earlier and later calendar years, subsidiary analyses were conducted on a cohort of 172 452 workers in the National Registry for Radiation Workers (NRRW) from the UK. A total of 18 310 incident first primary solid cancer cases were registered in the period from 1955 until 2011 in the NRRW cohort and workers accrued 5.25 million person-years of follow-up. Incidences rates of all solid cancers combined, lung cancer and solid cancer excluding lung cancer were examined in terms of external radiation doses in the full cohort and in a sub-cohort of workers who had no record of internal exposure monitoring and were defined by the periods of first hire before and after the beginning of the years 1960, 1965 and 1970. All analyses were carried out using Poisson Regression. These analyses demonstrated that only for lung cancer between the pre-1965 and post-1964 periods is there strong evidence for a difference in the risks using the NRRW full cohort. In the other calendar period breakdowns and for the other cancer groups, there is no clear evidence of differences in the risks. The NRRW estimation of risks between recent and early workers is not generally consistent with the US workers cohort or the INWORKS evaluations that later hired workers are at much higher solid cancer risk than earlier hired workers, although INWORKS contains a significant part of the latest updated NRRW cohort as well as the US data. The conclusion that the INWORKS and US study data demonstrate a real difference in excess solid cancer risk from external radiation exposure between earlier and later workers is premature. The results presented here should also be treated with caution because of the limited corroborating evidence from other published studies. Information on internal doses, neutron doses as well as non-radiation factors such as smoking and asbestos exposure would be needed to make definitive inferences.

Comparison of lifetime mortality risk, incidence risk, and DALYs of baseline cancer rates among countries as a benchmark for radiation-related cancer risk.

Statistical benchmark data are necessary when considering the basis for radiation protection criteria based on calculated risks. We herein focused on baseline mortality and incidence cancer rates as benchmark data collected from 33 countries. Furthermore, we calculated the lifetime mortality and incidence risks and disability-adjusted life years (DALYs) for all solid cancers, colon cancer, lung cancer, breast cancer, thyroid cancer, and leukemia using the baseline cancer rates and compared them among the countries. The results showed that the lifetime mortality and incidence risks and DALYs for all solid cancers differed among the countries by a factor of 2-4 for males and 2-3 for females; these were low in less-developed countries. Our study proposed that health risk based on baseline cancer rates should be the benchmark for comparing radiation cancer risks.

Combined effects of radiation and simulated microgravity on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice.

Explorations of the Moon and Mars are planned as future manned space missions, during which humans will be exposed to both radiation and microgravity. We do not, however, know the health effects for such combined exposures. In a ground-based experiment, we evaluated the combined effects of radiation and simulated microgravity on tumorigenesis by performing X-irradiation and tail suspension in C3B6F1 ApcMin/+ mice, a well-established model for intestinal tumorigenesis. Mice were irradiated at 2 weeks of age and underwent tail suspension for 3 or 11 weeks using a special device that avoids damage to the tail. The tail suspension treatment significantly reduced the thymus weight after 3 weeks but not 11 weeks, suggesting a transient stress response. The combination of irradiation and tail suspension significantly increased the number of small intestinal tumors less than 2 mm in diameter as compared with either treatment alone. The combined treatment also increased the fraction of malignant tumors among all small intestinal tumors as compared with the radiation-only treatment. Thus, the C3B6F1 ApcMin/+ mouse is a useful model for assessing cancer risk in a simulated space environment, in which simulated microgravity accelerates tumor progression when combined with radiation exposure.

Simulated galactic cosmic radiation-induced cancer progression in mice.

Prolonged manned space flight exposure risks to galactic comic radiation, has led to uncertainties in a variety of health risks. Our previous work, utilizing either single ion or multiple ion radiation exposure conducted at the NSRL (NASA Space Radiation Laboratory, Brookhaven, NY) demonstrated that HZE ion components of the GCR result in persistent inflammatory signaling, increased mutations, and higher rates of cancer initiation and progression. With the development of the 33-beam galactic cosmic radiation simulations (GCRsim) at the NSRL, we can more closely test on earth the radiation environment found in space. With a previously used lung cancer susceptible mouse model (K-rasLA-1), we performed acute exposure experiments lasting 1-2 h, and chronic exposure experiments lasting 2-6 weeks with a total dose of 50 cGy and 75 cGy. We obtained histological samples from a subset of mice 100 days post-irradiation, and the remaining mice were monitored for overall survival up to 1-year post-irradiation. When we compared acute exposures (1-2 hrs.) and chronic exposure (2-6 weeks), we found a trend in the increase of lung adenocarcinoma respectively for a total dose of 50 cGy and 75 cGy. Furthermore, when we added neutron exposure to the 75 cGy of GCRsim, we saw a further increase in the incidence of adenocarcinoma. We interpret these findings to suggest that the risks of carcinogenesis are heightened with doses anticipated during a round trip to Mars, and this risk is magnified when coupled with extra neutron exposure that are expected on the Martian surface. We also observed that risks are reduced when the NASA official 33-beam GCR simulations are provided at high dose rates compared to low dose rates.

If You Torture Your Data Long Enough, It Will Confess to Anything: On the Epidemiological Basis of the LNT Model.

This note deals with epidemiological data interpretation supporting the linear no-threshold model, as opposed to emerging evidence of adaptive response and hormesis from molecular biology in vitro and animal models. Particularly, the US-Japan Radiation Effects Research Foundation's lifespan study of atomic bomb survivors is scrutinized. We stress the years-long lag of the data processing after data gathering and evolving statistical models and methodologies across publications. The necessity of cautious interpretation of radiation epidemiology results is emphasized.

A Revised System of Radiological Protection Is Needed.

ABSTRACT: The system of radiological protection has been based on linear no-threshold theory and related dose-response models for health detriment (in part related to cancer induction) by ionizing radiation exposure for almost 70 y. The indicated system unintentionally promotes radiation phobia, which has harmed many in relationship to the Fukushima nuclear accident evacuations and led to some abortions following the Chernobyl nuclear accident. Linear no-threshold model users (mainly epidemiologists) imply that they can reliably assess the cancer excess relative risk (likely none) associated with tens or hundreds of nanogray (nGy) radiation doses to an organ (e.g., bone marrow); for 1,000 nGy, the excess relative risk is 1,000 times larger than that for 1 nGy. They are currently permitted this unscientific view (ignoring evolution-related natural defenses) because of the misinforming procedures used in data analyses of which many radiation experts are not aware. One such procedure is the intentional and unscientific vanishing of the excess relative risk uncertainty as radiation dose decreases toward assigned dose zero (for natural background radiation exposure). The main focus of this forum article is on correcting the serious error of discarding risk uncertainty and the impact of the correction. The result is that the last defense of the current system of radiological protection relying on linear no-threshold theory (i.e., epidemiologic studies implied findings of harm from very low doses) goes away. A revised system is therefore needed.

COVID-19 and cancer risk arising from ionizing radiation exposure through CT scans: a cross-sectional study.

BACKGROUND: The surge in the utilization of CT scans for COVID-19 diagnosis and monitoring during the pandemic is undeniable. This increase has brought to the forefront concerns about the potential long-term health consequences, especially radiation-induced cancer risk. This study aimed to quantify the potential cancer risk associated with CT scans performed for COVID-19 detection. METHODS: In this cross-sectional study data from a total of 561 patients, who were referred to the radiology center at Imam Hossein Hospital in Shahroud, was collected. CT scan reports were categorized into three groups based on the radiologist's interpretation. The BEIR VII model was employed to estimate the risk of radiation-induced cancer. RESULTS: Among the 561 patients, 299 (53.3%) were males and the average age of the patients was 49.61 ± 18.73 years. Of the CT scans, 408 (72.7%) were reported as normal. The average age of patients with normal, abnormal, and potentially abnormal CT scans was 47.57 ± 19.06, 54.80 ± 16.70, and 58.14 ± 16.60 years, respectively (p-value < 0.001). The average effective dose was 1.89 ± 0.21 mSv, with 1.76 ± 0.11 mSv for males and 2.05 ± 0.29 mSv for females (p-value < 0.001). The average risk of lung cancer was 3.84 ± 1.19 and 9.73 ± 3.27 cases per 100,000 patients for males and females, respectively. The average LAR for all cancer types was 10.30 ± 6.03 cases per 100,000 patients. CONCLUSIONS: This study highlights the critical issue of increased CT scan usage for COVID-19 diagnosis and the potential long-term consequences, especially the risk of cancer incidence. Healthcare policies should be prepared to address this potential rise in cancer incidence and the utilization of CT scans should be restricted to cases where laboratory tests are not readily available or when clinical symptoms are severe.

Risk of thoracic soft tissue sarcoma after breast cancer radiotherapy: a population-based cohort study in Osaka, Japan.

Postoperative radiotherapy for breast cancer reportedly increases the risk of thoracic soft tissue sarcomas, particularly angiosarcomas; however, the risk in the Japanese population remains unknown. Therefore, this study aimed to investigate the incidence of thoracic soft tissue sarcoma among patients with breast cancer in Japan and determine its association with radiotherapy. This retrospective cohort study used data from the population-based cancer registry of the Osaka Prefecture. The inclusion criteria were female sex, age 20-84 years, diagnosis of breast cancer between 1990 and 2010, no supraclavicular lymph node or distant metastasis, underwent surgery and survived for at least 1 year. The primary outcome was the occurrence of thoracic soft tissue sarcomas 1 year or later after breast cancer diagnosis. Among the 13 762 patients who received radiotherapy, 15 developed thoracic soft tissue sarcomas (nine angiosarcomas and six other sarcomas), with a median time of 7.7 years (interquartile range, 4.0-8.6 years) after breast cancer diagnosis. Among the 27 658 patients who did not receive radiotherapy, four developed thoracic soft tissue sarcomas (three angiosarcomas and one other sarcoma), with a median time of 11.6 years after diagnosis. The 10-year cumulative incidence was higher in the radiotherapy cohort than in the non-radiotherapy cohort (0.087 vs. 0.0036%, P < 0.001). Poisson regression analysis revealed that radiotherapy increased the risk of thoracic soft tissue sarcoma (relative risk, 6.8; 95% confidence interval, 2.4-24.4). Thus, although rare, breast cancer radiotherapy is associated with an increased risk of thoracic soft tissue sarcoma in the Japanese population.

Cancer Risk in Graves Disease with Radioactive 131I Treatment: A Nationwide Cohort Study.

Radioactive 131I (RAI) therapy has potential effects for the treatment of Graves disease (GD). However, whether RAI therapy for GD increases cancer risk remains controversial in medicine and public health. We aimed to investigate whether the risk of cancer increases in patients with GD receiving RAI therapy compared with those who did not. Methods: We used the Korean National Health Insurance Service's National Health Information Database from 2004 to 2020 and defined GD as prescribing antithyroid drugs, RAI, or thyroidectomy as a treatment for GD (International Classification of Diseases, 10th revision, E05 group). We investigated the hazard ratios (HRs) of overall and site-specific cancers associated with RAI in patients with GD. Subsequent cancer was defined as a primary malignancy treated at least 1 y after RAI therapy. Results: In total, 10,737 patients with GD who received RAI therapy (7,193 women, 67.0%; mean age, 43.7 ± 13.4 y) were matched to 53,003 patients with GD who had never received RAI treatment (35,471 women, 66.9%; mean age, 43.8 ± 13.2 y) in a 1:4-5 ratio by age, sex, and health checkup data. The median follow-up duration was 8.7 y (interquartile range, 5.2-12.1 y), and the median cumulative RAI dose was 555 MBq (interquartile range, 370-630 MBq) in the RAI therapy group. During 2004-2020, the overall subsequent cancer rates were 5.66 and 5.84 per 1,000 person-years in the RAI and non-RAI groups, respectively, with an unadjusted HR of 0.97 (95% CI, 0.88-1.06); this remained at 0.96 (95% CI, 0.83-1.10) after adjustment for multiple clinical confounding factors. For cancer subtypes, the risk of leukemia was significantly increased, with an HR of 2.39 (95% CI, 1.17-4.91). However, a loss of statistical significance was observed after adjusting for confounding factors, which may be attributed to the limited number of absolute events. Moreover, cancer-specific mortality was not different between the RAI and the non-RAI groups, with an adjusted HR of 0.99 (95% CI, 0.66-1.47). Conclusion: This study identified that the overall cancer risk in patients with GD who received RAI therapy compared with those who did not was not significant in Korea. Further long-term studies are needed to determine the risks and advantages of RAI therapy in patients with GD.

Radiation Therapy Technology Advances and Mitigation of Subsequent Neoplasms in Childhood Cancer Survivors.

PURPOSE: In this Pediatric Normal Tissue Effects in the Clinic (PENTEC) vision paper, challenges and opportunities in the assessment of subsequent neoplasms (SNs) from radiation therapy (RT) are presented and discussed in the context of technology advancement. METHODS AND MATERIALS: The paper discusses the current knowledge of SN risks associated with historic, contemporary, and future RT technologies. Opportunities for research and SN mitigation strategies in pediatric patients with cancer are reviewed. RESULTS: Present experience with radiation carcinogenesis is from populations exposed during widely different scenarios. Knowledge gaps exist within clinical cohorts and follow-up; dose-response and volume effects; dose-rate and fractionation effects; radiation quality and proton/particle therapy; age considerations; susceptibility of specific tissues; and risks related to genetic predisposition. The biological mechanisms associated with local and patient-level risks are largely unknown. CONCLUSIONS: Future cancer care is expected to involve several available RT technologies, necessitating evidence and strategies to assess the performance of competing treatments. It is essential to maximize the utilization of existing follow-up while planning for prospective data collection, including standardized registration of individual treatment information with linkage across patient databases.

[Radiation-induced parotid leiomyosarcoma]. / Léiomyosarcome parotidien en territoire irradié.

INTRODUCTION: First case of radiation-induced parotid leiomyosarcoma. ANATOMO-CLINICAL OBSERVATION: A 50-year-old woman with a history of cervical irradiation for Hodgkin's lymphoma presented with a right parotid tumefaction. Examination noted a deep adherent pretragal mass with peripheral facial palsy. A total parotidectomy with intra-operative examination and cervical curage was performed. Histopathological analysis concluded to a grade 3 parotid leiomyosarcoma according to the National Federation of Cancer Centers. Adjuvant radiotherapy was performed. After 24 months of follow-up, the patient presented bone and liver metastases without local recurrence. DISCUSSION: This is the first case of radiation-induced leiomyosarcoma and the 12th case of parotid leiomyosarcoma described in the literature. The management associates surgery with adjuvant radiotherapy. Follow-up is by clinical examination, parotid MRI, and annual thoracoabdominal CT scan to search for metastases. Recurrences occur during the first year in 40 to 64% of cases, and distant metastases in 40 to 60% of cases. The 5-year survival rate is between 10 and 30%.

Shape of radiation dose response relationship for ischaemic heart disease mortality and its interpretation: analysis of the national registry for radiation workers (NRRW) cohort.

Statistically significant increases in ischemic heart disease (IHD) mortality with cumulative occupational external radiation dose were observed in the National Registry for Radiation Workers (NRRW) cohort. There were 174 541 subjects in the NRRW cohort. The start of follow up was 1955, and the end of the follow-up for each worker was chosen as the earliest date of death or emigration, their 85th birthday or 31 December 2011. The dose-response relationship showed a downward curvature at a higher dose level >0.4 Sv with the overall shape of the dose-response relationship best described by a linear-quadratic model. The smaller risk at dose >0.4 Sv appears to be primarily associated with workers who started employment at a younger age (<30 years old) and those who were employed for more than 30 years. We modelled the dose response by age-at-first exposure. For the age-at-first exposure of 30+ years old, a linear dose-response was the best fit. For age-at-first exposure <30 years old, there was no evidence of excess risk of IHD mortality for radiation doses below 0.1 Sv or above 0.4 Sv, excess risk was only observed for doses between 0.1-0.4 Sv. For this age-at-first exposure group, it was also found that the doses they received when they were less than 35 years old or greater than 50 years old did not contribute to any increased IHD risk.

Solar ultraviolet radiation exposure, and incidence of childhood acute lymphocytic leukaemia and non-Hodgkin lymphoma in a US population-based dataset.

BACKGROUND: Acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) are among the commonest types of childhood cancer. Some previous studies suggested that elevated ultraviolet radiation (UVR) exposures increase ALL risk; many more indicate NHL risk is reduced. METHODS: We assessed age<20 ALL/NHL incidence in Surveillance, Epidemiology and End Results data using AVGLO-derived UVR irradiance/cumulative radiant exposure measures, using quasi-likelihood models accounting for underdispersion, adjusted for age, sex, racial/ethnic group and other county-level socioeconomic variables. RESULTS: There were 30,349 cases of ALL and 8062 of NHL, with significant increasing trends of ALL with UVR irradiance (relative risk (RR) = 1.200/mW/cm2 (95% CI 1.060, 1.359, p = 0.0040)), but significant decreasing trends for NHL (RR = 0.646/mW/cm2 (95% CI 0.512, 0.816, p = 0.0002)). There was a borderline-significant increasing trend of ALL with UVR cumulative radiant exposure (RR = 1.444/MJ/cm2 (95% CI 0.949, 2.197, p = 0.0865)), and significant decreasing trends for NHL (RR = 0.284/MJ/cm2 (95% CI 0.166, 0.485, p < 0.0001)). ALL and NHL trend RR is substantially increased among those aged 0-3. All-age trend RRs are most extreme (increasing for ALL, decreasing for NHL) for Hispanics for both UVR measures. CONCLUSIONS: Our more novel finding, of excess UVR-related ALL risk, is consistent with some previous studies, but is not clear-cut, and in need of replication.