British Journal of Radiology (2004) 77, 986-990
© 2004 British Institute of Radiology
doi: 10.1259/bjr/21023216
Second cancers following radiotherapy: a suggested common dosimetry framework for therapeutic and concomitant exposures
R M Harrison, PhD, FIPEM, FInstP
Regional Medical Physics Department, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE, UK
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Introduction
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Radiotherapy has always involved the unavoidable irradiation of organs and tissues outside the target volume. Consequently, delivery of the prescribed target dose whilst minimizing the dose to surrounding critical organs is a key objective of treatment planning. One of the detrimental effects of unwanted irradiation of critical organs is the probability of induction of a second cancer. This commentary is intended to draw attention to the difficulty of estimating second cancer risk following radiotherapy, including the contribution from concomitant exposures arising from treatment simulation and verification. It is suggested that effective dose is an unsatisfactory quantity in these circumstances and that estimates of probability of subsequent cancer would be more appropriate. In view of the large uncertainties in absolute risk estimation, it is suggested that concomitant organ doses and risks are assessed relative to the corresponding doses and risks from the therapeutic exposure. Because concomitant exposures are an essential and integral part of the overall treatment regimen, it is also suggested that separate specification and justification of individual concomitant exposures, for the purposes of compliance with the UK IR(ME)R 2000 Regulations [1] is unnecessary, provided that a dose "envelope" for the entire treatment regimen has been justified prior to treatment.
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Second cancer risk following radiotherapy
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There are numerous examples of epidemiological studies of second cancers following radiotherapy of the primary tumour and a comprehensive evaluation has been given by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) [2]. The National Radiological Protection Board (NRPB) has compared second cancer risks from radiotherapy with site-specific risks of radiation-induced cancer drawn from the Japanese atomic bomb survivor Life Span Study (LSS) [3]. NRPB calculated the excess relative risks (ERR) from radiotherapy treatment data and compared these with ERRs from matched groups taken from the LSS and showed that generally, the ERRs following radiotherapy were compatible with, or less than those from the LSS. Although differences may be masked by large confidence limits in the LSS data caused by the necessary sub-division of these data into cancers of different types, lower cancer risks observed in the radiotherapy data are compatible with cell kill at higher doses, perhaps counter-balanced to some extent by cellular re-population. There are several other potentially confounding factors, including differences in underlying cancer rates in the two populations studied, genetic predisposition to spontaneous cancer, fractionation, and the combination of radiotherapy with adjuvant chemotherapy (although evidence for risk modification due to this factor was weak). Nevertheless, in the absence of further data, it seems that the relative risks derived from the LSS could also be used, with caution, as upper limits to the risks following radiotherapy.
There is also a calculable probability of second cancer induction arising from concomitant exposures such as CT, simulator and portal imaging. The introduction of the IR(ME)R 2000 regulations in the UK [1] and the need to demonstrate that dose optimization has been achieved, has led to the requirement by IR(ME)R inspectors that doses from concomitant exposures must be separately assessed and justified. This has led to counter-arguments [4] that these concomitant doses are so small in comparison with the therapeutic doses that their separate estimation and documentation cannot be justified in the face of more pressing workload requirements. Without wishing to detract from the more general arguments advanced in his paper [4], Munro compares a skin dose from a CT scan with a target dose from radiotherapy. Because these doses refer only to two specific tissues, neither provides sufficient information to estimate the overall probability of a second cancer, which presumably is the point of dose estimation in these circumstances. The dose quantity most frequently used to unify risk assessment under different irradiation conditions is effective dose, and it is therefore worth examining the validity of this concept in the radiotherapy context.
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Effective dose
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Effective dose (E), was adopted by the International Commission on Radiological Protection (ICRP) [5] following its introduction by Jacobi [6].
E is given by: 
and
where E is the effective dose; wT is the tissue weighting factor for organ or tissue T; and HT is the equivalent dose to organ or tissue T.
Values of wT have been recommended by ICRP [5] and are based on the concept of detriment. Detriment includes contributions from several effects: the probability of fatal cancer for various organs, differences in latency leading to different values of relative length of life lost per fatal cancer (averaged over sex, exposure, age, population and risk model), morbidity resulting from induced non-fatal cancers and the risk of serious hereditary disease. From these, it can be seen that the detriment associated with a particular organ or tissue may be different for different exposed populations. Drexler et al [7] point out the limitations of comparing effective dose in populations that may have different age and sex distributions, bearing in mind that tissue weighting factors were derived for a working population and for both sexes. Populations of patients undergoing radiotherapy may have different age and sex distributions from the working population used, so that the use of current ICRP tissue weighting factors may be inappropriate, notwithstanding the apparent similarity between ERRs derived from radiotherapy and the LSS [3]. To illustrate this, Figure 1 shows the skewed age distribution of patients presenting with newly-diagnosed cancers in the UK in 2000 (S Rowan, private communication).
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Figure 1. Cancer incidence in England 1996–2000; all cancers (excluding non-melanoma skin cancer), by sex and single year of age at diagnosis. Courtesy of Dr S Rowan, London, Office for National Statistics 2003.
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A further complication is the remainder organ concept. The weighting factor for a remainder organ depends on whether the dose received by the organ is greater or less than the highest dose received by any of the organs for which an individual tissue weighting factor has been ascribed. It is conceivable that a remainder organ dose might fall into both categories when combining therapeutic and concomitant doses in radiotherapy and this dose dependence would make effective dose a non-additive quantity, although this may not be the case if new ICRP recommendations are adopted (currently in draft form: http://www.icrp.org/icrp_rec_june.asp).
It would be useful to explore alternative quantities to effective dose for use in the radiotherapy context. One possibility is simply the probability of second cancer induction – defined only for organs and tissues to which ICRP has ascribed a weighting factor (ICRP 60 [5] based cancer risks on mortality data, whereas new draff recommendations suggest that cancer incidence data are preferred). The issues and problems arising from the estimation of this quantity for both therapeutic and concomitant imaging exposures are discussed below.
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Estimates of the probability of second cancer induction following radiotherapy exposures
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The estimation of second cancer probability following radiotherapy is not trivial. The assumptions made in probability estimation for occupational, or other low dose situations, may not be valid for the higher doses received during radiotherapy. Within the target volume and conceivably for critical organs close to it, high cell kill and deterministic effects will occur and it is not clear how current methods, which deal exclusively with the stochastic effects due to low doses, can be modified to account for the high doses within the target volume and the high dose gradients at the periphery of, or just outside, the target volume.
At high doses, the effects of cell kill will be important, as pointed out by Mole [8]. A simple model, which incorporates cell kill, may be envisaged by reducing the overall probability of cancer induction by multiplication by the surviving fraction of cells. If the probability estimate of cancer induction assumes an intact and complete organ, then this probability may be assumed to be reduced in proportion to the cell kill.
In this case, the total probability of cancer induction Rtotal may be written as:
where ST is the surviving fraction of viable cells following a dose equivalent HT, i.e.
where fT is the probability of cancer induction in tissue T whose radiosensitivity is described by the factors 
T and 
T.
However, this model ignores re-population effects considered by Wheldon et al [9] and Lindsay et al [10]. They modelled radiation carcinogenesis for second tumours following radiotherapy, taking into account mutation rate, intrinsic and mutational radiosensitivities and assuming that re-population occurs according to a combination of Gompertzian and exponential growth functions (a "Gomp-ex" function) [11]. The results are illustrated in Figure 2, taken from [10], which is included to illustrate the general shape of the dose–incidence curves resulting from this approach. Note, however, that single, rather than fractionated, exposures were simulated. Key points in this work are:
- a wide range of curves may be generated depending on intrinsic radiosensitivity, mutational radiosensitivity, mutation rate, growth impairment and differential re-population rate, as well as the assumptions inherent in the "Gomp-ex" model of re-population. Few of these parameters are known accurately for particular human organs and tissues;
- the inclusion of re-population effects tends to skew curves to the high doses, in comparison with the cruder model given in Equation 1
, which simply modulates the (linear) dose–risk relationship with a term which relates surviving fraction to dose. (The latter is effectively the same as the model of Wheldon et al, but with no re-population).
A key feature of this, and similar work, is the hypothesis that the probability of second cancer induction first increases with increasing dose, reaches a peak and then decreases due to cell kill effects. However, only a few studies have been able to link specific organ and tissue doses to subsequent cancers. For example, Dörr and Herrmann [12] reported the relationship between the location of a second cancer and the dose received at that position from radiotherapy of the primary tumour. They found that the majority of second tumours were seen from 2.5 cm inside to 5 cm outside the planning target volume (PTV), in a region receiving <6 Gy. This is qualitatively consistent with the idea that the dose–response relationship is peaked.
However, there are confounding observations. Dörr and Herrmann's results show second cancers induced following doses as high as 65 Gy. Hall and Wuu [13], summarizing work by Boice et al [14] and Brenner et al [15], point out that the relative risk of induction of bladder cancer following radiotherapy for carcinoma of the cervix and prostate, respectively, does not appear to change significantly with dose over the range 2–80 Gy.
Nevertheless, in the absence of data on more organs and over wider, fractionated dose ranges, it is difficult to apply the model of Wheldon et al, or to interpret the "flat" dose response of some organs with confidence. The ICRP cancer induction probabilities and their implicit linear dependence on dose, may still be the most appropriate at the present time. In view of the high cell kill within the target volume, it may be reasonable to assume that the probability of a second cancer within this volume (say, the clinical target volume (CTV)) is negligible (say, <0.01% for a total dose of 60–70 Gy). The uncertainties in estimates of radiation carcinogenesis due to lack of basic knowledge and averaging over age and sex is acknowledged by ICRP and compounded by ignorance of how the probability of a second cancer might be influenced by the primary cancer and its treatment.
A practical point when considering justification of a therapeutic or concomitant exposure is the life expectancy of the patient in relation to the latent period for expression of a second cancer. Survival data will indicate the former, although latent periods are harder to estimate. Nevertheless, the second cancer risk for patients with life expectancies of, say, the order of a few months must be extremely small, irrespective of the dose delivered.
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Estimates of the probability of second cancer induction following concomitant exposures
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In estimating second cancer probabilities from concomitant exposures, we are on safer ground, since the doses concerned are much lower than the radiotherapy target doses and application of the probabilities of cancer induction given by ICRP has the same validity as in its ubiquitous use in occupational radiation protection and diagnostic radiology. Nevertheless, the problems of using an age distribution of a working population, rather than that of radiotherapy patients, still applies, as does the applicability or otherwise of the concept of detriment, if effective dose is used.
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Estimates of the combined second cancer induction probabilities following radiotherapy and imaging
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Because absolute probability estimates are subject to large uncertainties, relative probability estimates, i.e. the ratio of probabilities of cancer induction for therapy and concomitant exposures, might be useful in placing concomitant exposures in perspective. A rough guide to this ratio may be obtained from estimates of whole body dose equivalents (roughly comparable with effective dose) given by Followill et al [16] for tomotherapy, multileaf collimator (MLC)-modulated and conventional radiotherapy treatments. Taking their value of 911 mSv whole body dose equivalent for an 18 MV MLC treatment delivering 70 Gy at the isocentre and effective doses from, say, four abdomen and four pelvic CT examinations (to cover localization and verification) totalling 80 mSv, shows that the concomitant effective dose is approximately 9% of the therapy effective dose in this example. By implication, this contributes 9% of the risk of fatal second cancer induction. Clearly, this estimate must be very approximate, since organ doses were not measured by Followill et al [16] and effective dose is used to estimate the concomitant risk. Furthermore, the number of localization and verification episodes may vary considerably, and would be greater than given in this example in techniques such as image guided radiotherapy, where CT verification might be carried out at every fraction. Nevertheless, this crude comparison will suffice as a rough estimate in the absence of more specific data. It is clear that more work is required to obtain more accurate estimates of organ dose for different treatment regimens. Indeed, Followill et al [16] estimate total whole body dose equivalents of 2637 mSv, 911 mSv and 326 mSv for tomotherapy, MLC-modulated and conventional treatments, respectively, at 18 MV, showing that differences in whole body dose equivalent between these radiotherapy techniques for the same isocentre dose can vary by as much as 2300 mGy – at least two orders of magnitude greater than the effective dose for an abdominal CT scan.
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Summary and proposals
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- Effective dose is an unsatisfactory quantity for use in radiotherapy and the use of probability of cancer induction, summed over organs to which an individual tissue weighting factor has been ascribed by ICRP, is suggested for both therapeutic and concomitant exposures. Remainder organs should be included only if they can be ascribed unambiguous probabilities of cancer induction. It is further suggested that the probabilities of cancer induction given by ICRP are used, in the absence of data tailored more closely to the population profiles of radiotherapy patients, in view of the reasonable correspondence shown by NRPB between ERRs from second cancer studies and approximately matched groups from the LSS.
- For radiotherapy exposures, it is suggested that cancer probabilities are summed over all organs and tissues apart from those contained within the CTV, for which it assumed, in the absence of sufficient quantitative risk data, that the probability of second cancer induction is negligible.
- Concomitant exposures are an essential and integral part of the overall treatment regimen. They are likely to represent a small but significant proportion of the total dose burden and risk resulting from treatment. Provided that appropriate dosimetry and quality assurance is performed on CT scanners, simulators and portal imaging systems, and that an upper limit to the number of concomitant exposures is defined for each course of treatment, it should be possible to justify the combined therapy and imaging exposures en bloc, taking into account probabilities of second cancer induction, life expectancy and latent period. Unless the upper limit is likely to be exceeded, justification of concomitant exposures on an individual basis would then seem to be unnecessary.
Received for publication July 21, 2004.
Revision received August 31, 2004.
Accepted for publication September 20, 2004.
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References
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- Ionising Radiation (Medical Exposure) Regulations. London: HMSO, 2000. SI No.1059.
- UNSCEAR. United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and effects of ionising radiation. Report to the General Assembly, with scientific annexes. Volume II: Effects. Vienna and New York: United Nations Publications, 2000.
- NRPB. Risks of second cancers in therapeutically irradiated populations. Documents of the NRPB; vol 11 no.1 Chilton, Didcot: National Radiological Protection Board, 2000.
- Munro AJ. Motes and beams: some observations on an IR(ME)R inspection in radiotherapy. Br J Radiol 2004;77:273–275.[Free Full Text]
- 1990 Recommendations of the International Commission on Radiological Protection. Pergammon Press. 0146-6453, 1991. Annals of the ICRP; vol 21.
- Jacobi W. The concept of effective dose; a proposal for the combination of organ doses. Radiat Environ Biophys 1975;12:101–9.[Medline]
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- Wheldon EG, Lindsay KA, Wheldon TE. The dose–response relationship for cancer incidence in a two-stage radiation carcinogenesis model incorporating cellular repopulation. Int J Radiat Biol 2000;76:699–710.[CrossRef][Medline]
- Lindsay KA, Wheldon EG, Deehan C, Wheldon TE. Radiation carcinogenesis modelling for risk of treatment-related second tumours following radiotherapy. Br J Radiol 2001;74:529–36.[Abstract/Free Full Text]
- Wheldon TE. Mathematical models in cancer research. In: Mould DRF, editor. Medical Science Series. Bristol and Philadelphia: Adam Hilger, 1988.
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- Boice JD Jr, Day NE, Anderson A, Brinton LA, Brown R, Choi NW, et al. Second cancers following radiation treatment for cervical cancer: an international collaboration among cancer registries. J Natl Cancer Inst 1985;74:955–75.
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