Cancer risk in 680 000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians

A much needed study, however the average estimation of radiation dose in millisieverts may be an underestimation. ARPANSA conducted a study of average radiation doses from scans in Australia 1994-1995. The results show that a brain CT scan can deliver a dose of as much as 11nillisieverts and abdominal.scans as much as 70 millisieverts. This study examined data beginning in 1985 when even higher doses might have been used.

Linda Walsh (a), Roy Shore (b), Anssi Auvinen (c), Thomas Jung (a) & Richard Wakeford (d).

(a) Federal Office for Radiation Protection, Germany. (b) Radiation Effects Research Foundation, Japan. (c) Radiation and Nuclear Safety Authority, Finland. (d) The University of Manchester, UK.

Mathews et al (1) report the findings of a record linkage study of cancer incidence among 680,000 people who first underwent CT scans (CTs) in Australia while less than 20 years of age. As contributors to the World Health Organisation (WHO) report on Health Risk Assessment (HRA) after the 2011 Fukushima nuclear accident (2), there are several points in the Mathews et al (1) paper that raise concerns for us. In particular, some features of the study design, the comparisons with other studies, the cancer types with the strongest associations, and indications of a very short latency for CT-associated solid cancer incidence.

Mathews et al (1) do not give reasons for the choice of 1985 for the start of CT examinations and follow-up. About half of the persons in the cohort entered at the start of follow-up with “unknown” CT exposure status but were classified as “unexposed”. The authors (1) discuss this exposure misclassification bias and state that it would lead to a "small downward bias in our estimates of the cancer risks from CT", but do not justify this statement or quantify the potential impact of bias. The authors could have verified and strengthened their results by conducting an analysis restricted to persons born after 1985. Even after 1985, several sources of CT exposure were missed including: “nearly all CT scans in state based tertiary hospitals” (because no individual bills for these were in the Medicare administration system); CTs after age 20 years (which may have been appreciable, since follow-up sometimes extended past age 40 years); and the extra doses when patients had retakes (e.g., because of patient movement, especially during the long scan times required during the earlier calendar years).

Matthews et al (1) state that their risk estimates for leukaemia are similar to those in the Life Span Study (LSS) of survivors of the Hiroshima and Nagasaki A-bombings. However the leukaemia risks in their Table 7 (1) showed no excess for exposures before the age of 10 years, then a significant excess for exposures between 10-19 years of age. This age at exposure pattern is notably different from those reported in other studies (e.g., the LSS (3)). For brain cancer and all solid cancers except brain cancer, their Table 5 shows highly significant excesses 1-4 years after first exposure. The finding of such pronounced excesses so soon after first exposure is most unusual, and a minimum latent period of five years is conventionally adopted for radiation-induced solid cancers for this reason (4).

Further, the significant excesses of melanoma and Hodgkin’s lymphoma seem implausible to us and suggest possible confounding or bias in the study since other, more statistically powerful studies have not shown radiation-associated excesses for these types of cancer (5). In contrast, no excess of breast cancer was reported, although young women are considered to be particularly sensitive to radiation-induced breast cancer.

The possibility of reverse causation (i.e., that the early symptoms of undetected cancer, or of factors that predispose to cancer, were the indications for the CT scans rather than the CT scans causing the cancers) is certainly important here. The early appearance after first CT scan of solid cancers, and the significant excesses of cancers not thought to be particularly associated with exposure to radiation while there is no excess of radiosensitive breast cancer, reinforces concern over this possibility. It is not clear to us why the authors (1) did not consider these patterns in their results to demand a circumspect interpretation.

Conflict of Interest Statement

LW, RS, AA and TJ have no conflicts of interests to declare. RW carries out consultancy work (including work for the nuclear industry).

References

1. Mathews JD, Forsythe AV, Brady Z et al Cancer risk in 680 000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013;346:f2360 doi: 10.1136/bmj.f2360

2. Health risk assessment from the nuclear accident after the 2011 Great East Japan Earthquake and Tsunami based on a preliminary dose estimation. WHO, 2013.
http://www.who.int/ionizing_radiation/pub_meet/fukushima_risk_assessment...

3. Hsu W-L, Preston DL, Soda M et al. The Incidence of Leukemia, Lymphoma and Multiple Myeloma among Atomic Bomb Survivors: 1950–2001, Radiation Research, 179(3):361-382. 2013.

4. United States National Research Council, Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII – Phase 2. United States National Academy of Sciences. National Academy Press: Washington DC, 2006
http://www.nap.edu/catalog/11340.html

5. United Nations Effects of Ionizing Radiation. United Nations Scientific Committee on the Effects of Atomic Radiation UNSCEAR 2006 Report. Volume I. Annex A: Epidemiological studies of radiation and cancer. United Nations, New York, 2008

This study highlights one of the main dilemmas of modern medicine; namely, the threshold at which a clinician performs an investigation, particularly where this involves receiving a radiation dose such as computed tomography scan. The dilemma lies between not missing significant pathology and not utilising resources unnecessarily plus potentially increasing the patient’s future risk of cancer. In most specialities there are guidelines, from a variety of bodies including the national institute of clinical excellence and national specialty societies, which help determine the investigative pathway of patients. However, individual patients often present with a constellation of signs, symptoms and risk factors which may not fit within the guidelines. An example would be the young patient with a strong family history of coronary disease and first degree relatives presenting with myocardial infarction or death below the age of 40, with very atypical chest pain which is clearly non-cardiac in nature. A further example would be the patient who is in complete remission from cancer but notices vague intermittent bloating in the abdomen despite being very well with a normal clinical examination, ultrasound abdomen and blood profile. Some clinicians may just re-assure the patient whilst others may perform a coronary CT angiogram in the former case and CT abdomen in the latter case. Often the real-world decision making is based partly on clinical judgement of the physician but also increasingly on managing expectations and re-assuring patients. Patients should be made aware of the dose of radiation they receive and what implications this has on their future risk of cancer so they can be fully informed about the risks and benefits of their chosen pathway.

This excellent study by Mathews et al, which strongly supports the ‘linear no threshold theory', has significant implications not only for diagnostic radiologists but also for radiotherapists as well. (1).

Rapid technological advances in radiation therapy has meant introduction of novel techniques before full evaluation of benefits and risks. Recent technologies such as Image guided radiotherapy (IGRT) and Intensity modulated radiation therapy (IMRT) has led to a significant increase in the amount of normal tissue being exposed to ‘low dose’ radiation. (2)(3).

For instance, IGRT involves more frequent imaging during a course of radiotherapy to ensure accurate delivery of radiotherapy. IMRT helps to protect selected normal tissues from high-dose radiation at the expense of a large amount of normal tissues receiving low-dose radiation. Whether the benefits of newer radiation technologies outweigh the excess radiation risks needs to be explored urgently, particularly in childhood and adolescent cancers. (2)(3).

References
1. Mathews JD, Forsythe AV, Brady Z, Butler MW, Goergen SK, Byrnes GB, et al. Cancer risk in 680 000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ. 2013 May 21;346:f2360. doi: 10.1136/bmj.f2360

2. Maraldo MV, Brodin NP, Aznar MC, Vogelius IR, Munck Af Rosenschöld P, Petersen PM, Specht L. Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma. Ann Oncol (2013) doi: 10.1093/annonc/mdt156.

3. Kim DW, Chung WK, Yoon M. Imaging doses and secondary cancer risk from kilovoltage cone-beam CT in radiation therapy. Health Phys. 2013 May;104(5):499-503. doi: 10.1097/HP.0b013e318285c685.