Introduction to radiation-induced cancer
The first case of a radiation-induced cancer in a radiology technologist who suffered from severe atrophic skin damage (roentgenoderm) was demonstrated in 1904. Since then, ionizing radiations have been established as one possible cause of cancer. Numerous radiologists in the first three decades of the twentieth century developed radiation-induced malignancies: either skin cancers as a consequence of late skin damage or leukaemia. The full extent of the risk of radiation carcinogenesis and its dependence on dose and exposed organ was only assessed after the long-term follow-up studies of the survivors of the A-bombs in Hiroshima and Nagasaki were established.
Molecular mechanisms of radiation carcinogenesis
Radiation-induced DNA damage preferentially causes deletions. Therefore, it is generally assumed that the inactivating mutation of tumour suppressor genes is the most probable mechanism of the induction of cancer by low radiation doses and that a single radiation track traversing the nucleus has a finite probability, albeit very low, of generating the specific DNA damage that results in cancer growth. This hypothesis supports the assumption that cancer risk increases proportionally with radiation dose without threshold . Yet, the conclusion that this mechanism excludes the possibility of a dose threshold has been debated very controversially. Other biological mechanisms such as low-dose hypersensitivity which may specifically eliminate cells harbouring DNA damage, and non-targeted radiation effects such as radiation-induced genomic instability, bystander effects, and immunological surveillance mechanisms may modify the consequences of direct radiation-induced transforming mutations. The complex mechanisms elicited by initial processes continue to be the subject of radiobiological research .
The A-bomb survivor lifespan study, cancer mortality, and cancer incidence
The dramatic experience of the people of Hiroshima and Nagasaki in 1945 initiated a programme for life-long follow-up of all A-bomb survivors. This is arguably the largest, most comprehensive, and most detailed epidemiological study ever performed. The results of this study are the main data source on which rules and regulations of radiation protection are based.
The Life Span Study (LLS) comprises 120,321 people, including about 54,000 atomic bomb survivors who were within 2.5 km of the hypocentre at the time of the explosion. Of the study population 52% was still alive in 1999, including >85% of the nearly 50,000 individuals who were children or adolescents in August 1945.
For >90% of the total study population, detailed information was collected by Japanese interviewers on their exact location at the moment of explosion. The dose assessment (called the DS 86) is based on Monte Carlo calculations of track passage from the source in the exploding bomb through the air and the buildings to the body of the individual, calculating mean organ doses for different critical organs.
The most significant long-term health damage observed in the LSS is a dose-dependent increased mortality from cancer . Among the 44,771 deceased members of the LLS cohort with dosimetric information, there were 9335 deaths from cancer and 582 deaths from leukaemia. By analysing the relationship with radiation exposure, it was concluded that until 1997, 440 cancer deaths (4%) and nearly 100 leukaemia deaths (15%) have been attributable to the radiation exposure. Significant dose relationships were found for death from leukaemia and carcinoma of the stomach, colon, lung, breast, oesophagus, bladder, ovary, and liver. Since, at the time of the last analysis nearly 50% of the cohort was still alive, it is not possible to make well-founded statements on the life-time risk of dying for people who were young at the time of exposure.
The publication of cancer incidence data 1958 to 1998  is the most comprehensive and detailed analysis of the late carcinogenic effects of radiation. Of the 17,448 cancer cases observed in this study, 7851 occurred in individuals who had received a dose of >0.005 Gy and thus were considered exposed. Of these 853, i.e. 11%, were attributable to the radiation exposure. For a person aged 70 exposed to 1 Gy at the age of 30, the excess relative risk (ERR) was 0.47 for all cancers combined (0.58 for females and 0.35 for males).
The Chernobyl accident
The Chernobyl accident in 1986 was the most severe accident in the civil use of nuclear energy, so far. In the aftermath, many thousands of rescue workers, called liquidators, who were spread all over the former Soviet Union, were concerned about possible health damage from the radiation they had been exposed to during and after the accident. It was impossible to set up a comprehensive research programme such as after the Hiroshima and Nagasaki bomb explosions which covered all affected people. However, several epidemiological studies have been initiated and continue to provide important information on health consequences which complement the information gathered from the bomb survivors . The liquidator studies as well as studies of populations living in areas of radioactive contamination from accidents and bomb tests will provide important comparisons of radiation risks in people with different background cancer rates and from low dose rate radiation exposure with those in Japanese bomb survivors.
The most important findings in the populations exposed by the Chernobyl accident relate to the massive epidemic of thyroid cancer among the young which, until 2002, has affected nearly 5000 people who were under 17 in 1986. The data could be well fitted to a no-threshold linear dose response relationship with an eightfold increase of risk after 1 Gy thyroid dose. The highest risk was in children under 4 years at exposure. In young adults, the risk was much lower. The Chernobyl thyroid cancer cases provide a unique opportunity for studying specific molecular alterations caused by radiation since >90% of cancers occurring in those born between 1980 and 1986 are radiation-induced, whereas <10% of those occurring in those born after 1987 are radiation-induced. So far, few of the patients have died from thyroid cancer or treatment-related complications; the overall prognosis appears good .
Patients treated for benign diseases
Up to the 1960s, more patients were treated with radiotherapy for non-cancer diseases than for cancer. Although the number of indications has been reduced, it is still employed in the treatment of a variety of painful degenerative joint disorders. Doses are less than 10% of those given to treat cancer; results are usually fast and persistent. Some of these treatments are regarded as obsolete today; for example, for conditions such as ankylosing spondylitis pharmacological treatment options are available which are more convenient to doctor and patient. Moreover, some treatments used in the past were associated with a significantly increased risk of leukaemia and cancer [6, 7] analysed the mortality of 14,554 patients irradiated for ankylosing spondylitis between 1935 and 1954. Among the 1582 recorded deaths, the most striking finding was a tenfold increase in fatal leukaemia: 52 patients, compared to five expected. Post-partum mastitis was a very successful indication for low-dose radiotherapy. If irradiated early, one or two 0.5 Gy fractions will abolish the inflammation within a day or two, no abscess develops, no antibiotics or surgery are required, and breast feeding can be resumed quickly. Yet in most countries, this indication for radiotherapy has been abandoned as the extraordinary radiosensitivity of the breast of young women with regard to cancer induction became apparent. Shore et al.  studied 601 American women who had been irradiated between 1940 and 1957 for acute post-partum mastitis with a median dose of 3.5 Gy. After a mean follow-up of 30 years, they observed 56 women with breast cancer, whereas according to observation of the patients’ sisters, only 32 would have been expected.
These observations led to the recommendation that indication, planning, and performance of radiotherapy for selected non-malignant diseases should be made with the same care as definitive radiotherapy for cancer, limiting field sizes, avoiding critical organs, and reducing radiation to the lowest effective dose.
Radon exposure of hard rock miners or in homes
The publication of a report in 1879 on lung diseases among the miners in Schneeberg (Saxony, Germany) is a milestone in the history of occupational medicine. Härting and Hesse  proved that miners working underground died from lung cancer, usually after about 20 years working underground. By cleaning the air by forced ventilation and the introduction of wet drilling, the cancer rate was significantly reduced within ten years. Lung cancer was caused by the exposure of the miners to the radioactive decay products of radon gas which attach to aerosols in the air, and are inhaled and deposited on the bronchial epithelial, irradiating the epithelial stem cells with α-particles.
Several large cohort studies of uranium miners confirmed the early findings. All types of lung cancer are increased in the uranium miners. There is a supra-additive interaction between exposure to radon and cigarette smoking, with silica dust in the mines also contributing to the cancer risk. The results of these studies suggest the possibility that exposure to radon in houses may cause lung cancer in the general population. Radon concentrations in houses vary by orders of magnitude and in some regions with special geological features they can reach values which cause concern. In several European countries and in China large case control studies on the contribution of radon exposure to the lung cancer risk have been performed. In the German study , nearly 3000 cases of lung cancer and 4200 controls were investigated. In addition to a comprehensive interrogation, radon concentration measurements were performed in current and previous homes. As expected, the most important risk factor for lung cancer was cigarette smoking. Despite this strong influence of smoking, a clear dependence of relative risk on radon concentration in homes was observed, as was also the case in studies in Finland, Sweden, and the UK. The overall excess lung cancer risk at a radon concentration of 100 Bq/m3 was 10%. The excess risk from radon was found to exist for smokers as well as for non-smokers, with the risks interacting in a multiplicative way. Up to 10% of all lung cancers may be caused by radon in homes.
Second cancers after cancer therapy
During the typical follow-up period of a patient treated for cancer with radical radiotherapy, many patients will present with a second cancer. The frequency varies between <1% and >10%, depending on age and sex. Results of epidemiological studies demonstrate that after radiotherapy, the increased lifespan of cured patients, and not direct radiation effects, is the most important underlying cause leading to second cancers.
The International Commission on Radiation Protection (ICRP) developed a method to estimate the risk of radiation-induced cancer from the occupational and environmental exposure of workers and the general population which has been also widely used in estimating risk of second cancers after radiotherapy of first cancers. Yet the ICRP  strongly advised against using this method to estimate the risks of radiation-induced cancer after radiotherapy since the dose distributions within and between organs are completely different. Second cancer risks estimated this way are orders of magnitude higher than those derived directly from epidemiological investigations on radiotherapy patients. The risk of radiation-induced second cancers should be estimated by the comparison of second cancer rates in patient cohorts who were cured from their first cancer by either radiotherapy or by surgery. This method avoids the influence of competing risks from underlying genetics and lifestyle which may differ between cancer patients and members of the general population. However, important information can also be derived from studies on the topographical relationship of primary and second cancer in symmetrical organs, in particular in patients with a primary breast cancer and a secondary lung cancer. Moreover, studies on second cancers after radiotherapy of young people and their comparison with age-matched healthy populations provide information after very long follow-up, but interpretation is difficult because of strong genetic susceptibility factors influencing risks. A comprehensive review by the National Council of Radiation Protection of the USA has been summarized by Travis et al. .
Carcinoma of the prostate
The results of the large cohort study on more than 120,000 prostate cancer patients registered in the SEER program who either had surgery or radiotherapy  demonstrate the extent of the problem for clinical radiotherapy well.
Of the approximately 17,000 prostate cancer patients who survived more than five years after radical radiotherapy, 1185 (7%) developed a second cancer. More than 1000 of those second cancers (>85%) are due to the increased lifespan after cure from the first cancer. Just about 120 to 150 of those second cancers among 51,584 prostate cancer patients (0.3%) are related to radiotherapy, in particular:
◆ approximately 50 cases of bladder cancer;
◆ approximately 15 cases of cancer of the rectum;
◆ approximately 50 cases of lung cancer;
◆ approximately 12 cases of leukaemia.
The most important message of the prostate cancer study is that half of all radiation-induced second cancers occur in the high-dose organs (bladder, rectum) and the other half in the organs exposed to low doses (lung). It is likely that different mechanisms are involved in the high- and low-dose organs. The mechanisms of low-dose radiation carcinogenesis have been explored in radiation protection research . On the other hand, high radiation doses may lead to chronic radiation injury characterized by microvascular damage, parenchymal atrophy and chronic inflammation, a typical pre-cancerous lesion.
Patients treated with post-operative radiotherapy for breast cancer receive significant radiation doses of more than 5% of the target dose to the contralateral breast. Since second cancers in the contralateral breast occur more frequently than expected and comprise nearly half of all second cancers in women with breast cancer, a causal relationship with the radiation exposure from the treatment of the first cancer was suggested. A case control study by Stovall et al.  embedded into the WECARE Study with 708 women with asynchronous bilateral breast cancer and 1399 women with unilateral breast cancer (controls) demonstrated that women <40 years of age who received >1Gy to the specific quadrant of the contralateral breast had a 2.5-fold greater risk for contralateral breast cancer than unexposed women. No excess was observed in women >40 years of age. It is particularly in young breast cancer patients that the dose to the contralateral breast should be carefully controlled.
Patients treated with post-operative radiotherapy for breast cancer receive very different doses to the ipsilateral compared to the contralateral lungs. Darby et al.  reported that among 115,165 women treated for breast cancer using radiotherapy 482 women died from lung cancer for which the affected side was clearly defined in the records. Of the cases, 283 (59%) were ipsilateral and 199 (41%) were contralateral. From these findings an absolute risk of 0.6% of radiation-induced lung cancer was estimated. Grantzau et al.  analysed the long-term risk of second primary solid non-breast cancers in the Danish national population-based cohort of more than 46,000 patients treated according to national guidelines of the Danish Breast Cancer Cooperative Group for early breast cancer between 1982 and 2007. About half received post-operative radiotherapy and were compared to those not receiving radiotherapy. Altogether, 2358 second cancers had occurred during the follow-up. The hazard ratio was not increased for sites distant from the treatment field; however, it progressively increased with duration of follow-up for sites in the thorax, in particular the lungs. The estimated attributable risk of developing a secondary cancer in the thorax (excluding contralateral breast) translates into one radiation-induced second cancer in every 200 women treated with radiotherapy.
Dores et al.  reported results of a large international study on 32,591 Hodgkin lymphoma patients with 2861 patients followed up for more than 20 years and 1111 patients for more than 25 years. Mean age at treatment was 37 years. Second malignancies developed in 2153 patients (7%) which, compared to the age- and sex-adjusted general population, was an increase of more than a factor of 2. The risk of late-developing solid cancers was particularly increased after radiotherapy while second leukaemias were mostly related to chemotherapy. The highest absolute excess second cancer risk was for cancers of the lung and breast. The authors calculated a 25-year cumulative risk of treatment-induced second cancers of 11.7%, most of which was related to radiotherapy.
In their review of late effects after treatment for Hodgkin lymphoma, Swerdlow and van Leeuwen  concluded that the substantial increase in solid tumour risk with time since diagnosis necessitated careful, lifelong medical surveillance of all patients. In particular, women treated with mantle field irradiation before the age of 30 are at greatly increased risk of breast cancer and follow-up of these women should include yearly mammography; however, the efficacy of these measures has not yet been demonstrated.
The chances of children with cancer being cured and having a near normal life-expectancy have reached a level unimaginable 30 years ago. But the price for this progress has been high. Neglia et al.  investigated a cohort of 13,581 children from the Childhood Cancer Survivor Study register in the USA who survived at least five years. After a mean latency of 12 years, 298 second malignancies were observed. Whereas the risk of secondary leukaemia (altogether 24 cases) increased to a peak after five to nine years, the risk of solid second cancers, in particular breast, thyroid, and CNS was significantly elevated during the entire follow-up period of up to 30 years. The study of de Vathaire et al.  specifically looked at the impact of radiotherapy on childhood solid malignancies on the risk of second cancers. They analysed the second cancer risk in 4400 three-year survivors treated in France and the UK, 3109 (71%) of whom received radiotherapy. For 2831 (91%) of these children, individual radiation doses at 151 points of the body were determined, based on the individual treatment plans using a computer phantom. Of these, 113 patients (4%) developed a solid second malignant tumour. Twenty-five years after treatment of the primary malignancy, the cumulative risk was 5%; five years later it approached 8%. In 543 patients who had already attained an age >30 years, 16 second cancers were diagnosed while only 3.3 were expected, a fivefold increase. Diallo et al.  analysed the anatomical relationship between the location of fatal second cancers and the anatomy of the planning target volume (PTV) for sarcomas, brain tumours, breast cancer, and thyroid cancer. Of fatal second cancers, 50% were sarcomas, nearly 90% developed in or close to the PTV while the majority of central nervous system tumours occurred at a distance from the PTV. Tukenova et al.  reported that sarcomas occurred earlier than carcinomas but stayed constant after 20 years while the rate of carcinomas continued to increase steadily with increasing follow-up time.
In a study on 102 second cancers among 930 children treated for Hodgkin disease, Constine et al.  reported a threefold higher risk for female children treated for Hodgkin disease than for males of developing second cancers. This is mainly due to the high rate of cancers of the breast, but also of thyroid carcinomas and of sarcomas in females. These three cancer types comprise three-quarters of all second cancers in female Hodgkin survivors. Second cancers after childhood cancer radiotherapy are a particularly serious problem in female patients.
In a comprehensive analysis of data stored in the US Surveillance, Epidemiology and End Results Cancer Registries, Berrington de Gonzalez et al.  determined the proportion of second cancers which are attributable to radiotherapy treatments in 647,672 adults who survived their first cancer for more than five years and were followed up for another seven years. Of these 60,271 (9%) developed a second solid cancer between five and 12 years after treatment of the first cancer. The relative risk of second cancer and the proportion of cancers attributable to radiotherapy were calculated by comparing cancer rates for patients receiving radiotherapy versus patients not receiving radiotherapy in the definitive treatment of 15 types of first malignancy. In total, an estimated 3266 excess solid cancers could be related to radiotherapy in these five-year survivors, i.e. 8% of the total second cancers diagnosed in the cancer survivors who had received radiotherapy. The authors estimated that for every 1000 patients treated with radiotherapy there were an estimated three excess cancers by ten years after first cancer diagnosis which increased to five excess cases by 15 years. Over half of the excess cases occurred in organs likely to have received >5 Gy. The risk of radiation-induced second cancers is much greater in young and very young cancer patients. Increased cancer rates may persist lifelong.
All estimates of treatment-related second cancers made above are inevitably based on retrospective analyses of results from treating patients many years ago, yet the situation has changed dramatically in radiation oncology during the last two decades. Today, patients rarely receive radiotherapy alone. In particular, studies in patients treated as children with chemotherapy plus radiotherapy demonstrated that both treatment modalities increase the risk of secondary malignancy in cured patients, both regarding leukaemias and solid cancers. Therefore, the risk of cancer induced by the combination of chemotherapy, radiotherapy, and novel molecular agents cannot be predicted from the results of these studies on past patients, and the combinatory effects need to be closely watched in future.
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