To our knowledge, this is the first study to estimate the proportion of second cancers overall in adult cancer survivors that might be related to radiotherapy treatment. Our results suggest that about 8% (95%CI:7%–9%) of second solid cancers may be related to the radiotherapy treatment for the first cancer. This figure varied according to first cancer site, from 4% for eye/orbit cancers to 24% for testicular cancer. Higher attributable risks were most likely due to younger age at treatment, larger treatment fields and the organs located in those fields. In general the relative risks decreased with increasing age, and increased with increasing time since diagnosis. By 15 years after diagnosis there were an estimated 5 excess cancers per 1000 patients treated with radiotherapy.
Although there have been a large number of studies of second cancers after radiotherapy treatment, few have assessed the attributable risk or cumulative absolute risk. We previously estimated that 5–6% of second solid cancers after breast cancer were related to radiotherapy in the SEER cancer registries.4
Using published results from the pooled analysis of randomized radiotherapy trials for breast cancer we estimated a similar attributable risk (8%), which suggests that our estimate was not subject to strong confounding by indication.14
In an earlier analysis of cervical cancer patients using cancer registries Boice et al estimated an attributable risk of 5%,15
which is considerably smaller than the estimate of 17% (95%CI: 10%–23%) in the current study. One possible reason for this difference was use of the general population as the comparison group in the previous study, due to the small number of patients who did not receive radiotherapy during that study’s time period. Also only cancers that were considered to be radiation-inducible were included in the excess, for example rectal cancers were excluded in the previous study but they are now considered to be radiation-inducible6
and were included here. In a previous study of prostate cancer radiotherapy using SEER registries Brenner et al estimated that there were 3 excess cancers/1000 patients in all survivors,.16
which is similar in magnitude to our overall estimate of 5 cancers/1000.
A number of previous studies have estimated the dose-response relationship for specific second solid cancers after radiotherapy based on individual treatment records. One such study of cervical cancer treatment found a positive dose-response relationship for second cancers of the bladder, rectum, bone, stomach and all female genital cancers combined after radiotherapy for cervical cancer.17
In breast cancer patients dose-response relationships have also been observed for lung, bone, connective tissue and contralateral breast cancers after radiotherapy,18–22
and for stomach cancer after testicular cancer and Hodgkin lymphoma.23
Although the site-specific risks were not the focus of the current study, the patterns of the risks were generally consistent with these previous reports (Webtable 1
). There is also a large body of evidence from registry based studies with more limited details on the radiotherapy treatment (yes/no and external beam/brachytherapy) and hospital series. These studies include a number of analyses of SEER registries that focused on a single first cancer. Our results were broadly consistent with those previous reports, which found that those treated with radiotherapy have a small (RR=1.1–1.4) increased risk of a second cancer overall compared to those who did not receive radiotherapy (Webtable 5
The strengths of the current study include the systematic approach used to assess all first cancer sites, which enabled comparisons of risks across first cancer sites and examination of common patterns of risk. The large sample size and long-term follow-up are also key strengths of the SEER registries for assessing the late-effects of radiotherapy, along with comprehensive coding rules for second cancers, which have changed minimally over time. We assessed the plausibility that the observed relationships were causal by examining the dose-response across groups of second cancer sites and the relationship with age at exposure and latency. Mostly these followed the expected patterns, i.e. higher relative risks for higher dose-sites, for younger ages at exposure and with longer time since diagnosis. Our dose-response analysis, however, was necessarily crude and sites were likely misclassified since we did not have individual treatment data on the radiotherapy fields used.
The main limitation of the SEER data, like any observational study of treatment effects, is the lack of treatment randomization and therefore the potential for confounding by indication. Confounding would occur if factors related to radiotherapy use were also related to the risk of second cancer. We used a number of approaches to try to minimize this and other potential biases. Firstly we excluded the first five years of follow-up from the analyses to reduce the potential impact of surveillance bias. We adjusted all analyses for likely confounding factors that were available including stage, age at diagnosis and year of diagnosis, attained calendar period and attained age. For some cancer sites receipt of radiotherapy rather than surgery may be associated with risk factors for second cancers like smoking if these risk factors are contra-indications for surgery. It was reassuring, therefore, that the results from the analysis restricted to patients who had had cancer related surgery were similar to those for all patients (+/−10%). In general though the relative risks were higher for second cancer sites that are smoking related.38
Lack of data on smoking and other treatments including chemotherapy and hormonal therapy treatment means that it is likely that there is some residual confounding. The level of confounding may vary across the first cancer sites as the characteristics of the patients who do not receive radiotherapy vary, and could have resulted in either over-estimation or under-estimation of the risks related to radiotherapy.
Our results are for patients treated in the U.S. over the last 30 years, and radiotherapy techniques have changed during this time period. For most sites, however, we did not find strong evidence of trends in the risks over calendar time (Webtable 4
). An unavoidable limitation of studying the late effects of radiotherapy is that the most recent changes in practice cannot be studied. In particular, as all the patients were treated before 2003 the impact of the widespread introduction of intensity modulated radiotherapy (IMRT) could not be evaluated. There is concern that IMRT might actually increase second cancer risks due to the increased volume of tissue that receives low-level exposure,39
and it will be important to study this question directly in the future. Nevertheless, we estimate that by fifteen years of follow-up the absolute risks for adults are typically only a few excess cancers per 1000 treated. Even if current practice substantially changed radiation doses to some organs, the general message that the second cancer risks from radiotherapy in adulthood are small, especially when compared with the treatment benefits, would remain the same.
In summary we found that a relatively small proportion of second cancers (<10%) in adult cancer survivors are likely to be related to radiotherapy, suggesting that most are due to other factors, such as lifestyle or genetics.
Research in Context
We searched Pubmed with key terms including “radiotherapy”, “secondary malignancy” and also terms for each of the fifteen 1st
cancer sites of interest. We also searched reference lists in previous articles. All key articles are described in the discussion and articles that had published relative risks for all second cancers or all second solid cancers are shown in Webtable 5
. Where more than one article was published from the same cohort we present results from the most recent publication. Only three of the previous studies had published estimates of the attributable risk for radiotherapy and only one had published estimates of the cumulative absolute risk. Our results were generally consistent with the existing evidence, where it was available. None of the previous studies had combined data from multiple first cancer sites.
Our results suggest that a relatively small proportion of second cancers (<10%) in adult cancer survivors are likely to be related to radiotherapy, suggesting that most are due to other factors, such as lifestyle or genetics. These findings can be used by physicians and patients to put the risk of radiation-related cancer into perspective when compared to the likely benefits of the treatment. Studies of the second cancer risks from newer radiotherapy treatments such as IMRT, however, are still required.