3D-CRT
Radiation-induced second cancers: the impact of 3D-CRT and IMRT☆

Presented at the 3rd S. Takahashi Memorial International Workshop on 3-Dimensional Conformal Radiotherapy, December 8–10, 2001, Nagoya, Japan.
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Abstract

Information concerning radiation-induced malignancies comes from the A-bomb survivors and from medically exposed individuals, including second cancers in radiation therapy patients. The A-bomb survivors show an excess incidence of carcinomas in tissues such as the gastrointestinal tract, breast, thyroid, and bladder, which is linear with dose up to about 2.5 Sv. There is great uncertainty concerning the dose–

response relationship for radiation-induced carcinogenesis at higher doses. Some animal and human data suggest a decrease at higher doses, usually attributed to cell killing; other data suggest a plateau in dose. Radiotherapy patients also show an excess incidence of carcinomas, often in sites remote from the treatment fields; in addition there is an excess incidence of sarcomas in the heavily irradiated in-field tissues. The transition from conventional radiotherapy to three-dimensional conformal radiation therapy (3D-CRT) involves a reduction in the volume of normal tissues receiving a high dose, with an increase in dose to the target volume that includes the tumor and a limited amount of normal tissue. One might expect a decrease in the number of sarcomas induced and also (less certain) a small decrease in the number of carcinomas. All around, a good thing. By contrast, the move from 3D-CRT to intensity-modulated radiation therapy (IMRT) involves more fields, and the dose–

volume histograms show that, as a consequence, a larger volume of normal tissue is exposed to lower doses. In addition, the number of monitor units is increased by a factor of 2 to 3, increasing the total body exposure, due to leakage radiation. Both factors will tend to increase the risk of second cancers. Altogether, IMRT is likely to almost double the incidence of second malignancies compared with conventional radiotherapy from about 1% to 1.75% for patients surviving 10 years. The numbers may be larger for longer survival (or for younger patients), but the ratio should remain the same.

Introduction

There is an abundance of data to indicate that radiation can induce cancer in the human. Indeed, radiation has been described as a “two-edged sword” because, while it is a major modality for the treatment of cancer, it can also be the cause of cancer.

Our knowledge of radiation-induced cancer comes from survivors of the A-bomb attacks on Japan; from radiation accidents; and from individuals medically exposed—and these include second cancers in patients receiving radiation therapy.

There are a number of interesting conclusions that emerge from the study of the A-bomb survivors. First, the malignancies observed are leukemias and carcinomas of the cells that line the body. Second, there is no excess of sarcomas. Third, the overall risk of fatal cancers is estimated to be 8%/Gy, i.e., if 100 individuals were exposed to 1 Gy, 8 would develop a fatal cancer due to the radiation, over and above the spontaneous incidence. Fourth, there is a very large variation of risk, with young children being about 15 times as sensitive as middle-aged adults.

There is an interesting difference in the second malignancies induced in patients by radiation therapy. First, carcinomas are observed in the lining cells of the body (much like the A-bomb survivors) and often in tissues and organs that received lower doses because they were remote from the treatment site. Second, sarcomas are induced in heavily irradiated tissues in or close to the radiation fields. This class of tumors was not seen in the A-bomb survivors who received doses of a few Gray.

Section snippets

Second malignancies in radiotherapy patients

The risk of second malignancies after radiotherapy is a subject not without controversy. One of the reasons for the uncertainty is that patients undergoing radiotherapy are often at high risk of a second cancer because of their lifestyles or genetic predisposition, which could be more dominant than the radiation risk.

There are many single-institution studies in the literature involving radiotherapy for a variety of sites that conclude that there was no increase in second malignancies, although

The impact of three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT)

Now to a consideration of the potential impact of the new technologies, such as 3D-CRT and IMRT, on the induction of second malignancies. There are two reasons why the change from 3D-CRT to IMRT may result in an increase in second malignancies. First, the change from 3D-CRT to IMRT involves the use of more fields, and as a consequence, a bigger volume of normal tissue is exposed to lower doses. Second, delivery of a specified dose to the isocenter from a modulated field, delivered by IMRT, will

Conclusions

A number of general conclusions can be drawn from the above discussion. First, concerning radiation-induced sarcomas, because these tumors occur only in heavily irradiated tissues, it is unlikely that a difference will be detected between 3D-CRT and IMRT, since the high dose volume is not much changed. Their absolute number is small if follow-up is short, but the number may increase dramatically for long life expectancy.

Second, concerning radiation-induced carcinomas, there is likely to be an

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☆

This work was supported by grant CA49062 awarded by the National Institutes of Health and grant NAG-9-1148 awarded by NASA.

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