Eric J. Hall

Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know

High doses of ionizing radiation clearly produce deleterious consequences in humans, including, but not exclusively, cancer induction. At very low radiation doses the situation is much less clear, but the risks of low-dose radiation are of societal importance in relation to issues as varied as screening tests for cancer, the future of nuclear power, occupational radiation exposure, frequent-flyer risks, manned space exploration, and radiological terrorism. We review the difficulties involved in quantifying the risks of low-dose radiation and address two specific questions. First, what is the lowest dose of x- or γ-radiation for which good evidence exists of increased cancer risks in humans? The epidemiological data suggest that it is ≈10–50 mSv for an acute exposure and ≈50–100 mSv for a protracted exposure. Second, what is the most appropriate way to extrapolate such cancer risk estimates to still lower doses? Given that it is supported by experimentally grounded, quantifiable, biophysical arguments, a linear extrapolation of cancer risks from intermediate to very low doses currently appears to be the most appropriate methodology. This linearity assumption is not necessarily the most conservative approach, and it is likely that it will result in an underestimate of some radiation-induced cancer risks and an overestimate of others.

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

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.

Fractionation and protraction for radiotherapy of prostate carcinoma

PURPOSE To investigate whether current fractionation and brachytherapy protraction schemes for the treatment of prostatic cancer with radiation are optimal, or could be improved. METHODS AND MATERIALS We analyzed two mature data sets on radiotherapeutic tumor control for prostate cancer, one using EBRT and the other permanent seed implants, to extract the sensitivity to changes in fractionation of prostatic tumors. The standard linear-quadratic model was used for the analysis. RESULTS Prostatic cancers appear significantly more sensitive to changes in fractionation than most other cancers. The estimated alpha/beta value is 1.5 Gy [0.8, 2.2]. This result is not too surprising as there is a documented relationship between cellular proliferative status and sensitivity to changes in fractionation, and prostatic tumors contain exceptionally low proportions of proliferating cells. CONCLUSIONS High dose rate (HDR) brachytherapy would be a highly appropriate modality for treating prostate cancer. Appropriately designed HDR brachytherapy regimens would be expected to be as efficacious as low dose rate, but with added advantages of logistic convenience and more reliable dose distributions. Similarly, external beam treatments for prostate cancer can be designed using larger doses per fraction; appropriately designed hypofractionation schemes would be expected to maintain current levels of tumor control and late sequelae, but with reduced acute morbidity, together with the logistic and financial advantages of fewer numbers of fractions.

Second Malignancies in Prostate Carcinoma Patients after Radiotherapy Compared with Surgery

In the treatment of prostate carcinoma, radiotherapy and surgery are common choices of comparable efficacy; thus a realistic comparison of the potential long term sequelae, such as the risk of second malignancy, may be of relevance to treatment choice.

Radiation oncology: a century of achievements

Over the twentieth century the discipline of radiation oncology has developed from an experimental application of X-rays to a highly sophisticated treatment of cancer. Experts from many disciplines — chiefly clinicians, physicists and biologists — have contributed to these advances. Whereas the emphasis in the past was on refining techniques to ensure the accurate delivery of radiation, the future of radiation oncology lies in exploiting the genetics or the microenvironment of the tumour to turn cancer from an acute disease to a chronic disease that can be treated effectively with radiation.

Conditions for the equivalence of continuous to pulsed low dose rate brachytherapy

Low dose rate interstitial brachytherapy is extremely useful for those tumors that are accessible for an implant, while the introduction of remote afterloaders has eliminated exposure to nursing personnel. Currently, such machines require an inventory of many sources which are loaded into catheters implanted in the tumor and kept in place during treatment. A significant simplification of such machines would be possible in a pulsed mode, with a single source moving under computer control through the catheters. Assuming that the treatment time and average dose rate are kept unchanged, the question addressed is to find those combinations of radiation pulse widths and frequencies that would be functionally equivalent to a continuous irradiation. The linear-quadratic formalism was used to reanalyze published low dose-rate studies on cells of human origin to obtain 36 parameter sets [alpha, beta, T1/2], where T1/2 is the half time for sublethal damage repair. These data are consistent with those for human tumors. For each parameter set, those combinations of pulse width and frequency were calculated that would yield a functionally equivalent cell survival. For a regimen of 30 Gy in 60 hr, a pulse width of 10 min with a period between pulses of 1 hr would be appropriate for all the cell lines considered. Similar results were found for other possible time/dose combinations. For late effects, a 1-hr period between 10-min pulses might produce up to a 2% increase in late-effect probability, which is probably acceptable for the small volumes irradiated in interstitial brachytherapy.

Taxol: A novel radiation sensitizer

The investigational antineoplastic agent, taxol, a natural product from the yew, Taxus sp. L., is currently being evaluated in a series of Phase II clinical trials. To date, the drug has shown activity against ovarian cancer, lung cancer, and melanoma. Taxol is a potent microtubule stabilizing agent that selectively blocks cells in the G2 and M phases of the cell cycle and is cytotoxic in a time-concentration dependent manner. It is well known from radiobiological principles that G2 and M are the most radiosensitive phases of the cell cycle. On the rationale that taxol could function as a cell-cycle selective radiosensitizer, we examined the consequences of combined drug-radiation exposures on the human grade 3 astrocytoma cell line, G18. Survival curve analysis shows a dramatic interaction between taxol and ionizing radiation with the degree of enhanced cell killing dependent on taxol concentration and on the fraction of cells in the G2 or M phases of the cell cycle. The sensitizer enhancement ratio (SER) for 10 nM taxol at 10% survival is approximately 1.8. These results obtained with cycling aerated radioresistant brain tumor cells indicate that significant advantage may derive from appropriate time-concentration dependent interactions in combined modality protocols.

The Bystander Effect in Radiation Oncogenesis: I. Transformation in C3H 10T½ Cells In Vitro can be Initiated in the Unirradiated Neighbors of Irradiated Cells

Abstract Sawant, S. G., Randers-Pehrson, G., Geard, C. R., Brenner, D. J. and Hall, E. J. The Bystander Effect in Radiation Oncogenesis: I. Transformation in C3H 10T½ Cells In Vitro can be Initiated in the Unirradiated Neighbors of Irradiated Cells. It has long been accepted that radiation-induced genetic effects require that DNA be hit and damaged directly by the radiation. Recently, evidence has accumulated that in cell populations exposed to low doses of α particles, biological effects occur in a larger proportion of cells than are estimated to have been traversed by α particles. The end points observed include chromosome aberrations, mutations and gene expression. The development of a fast single-cell microbeam now makes it possible to expose a precisely known proportion of cells in a population to exactly defined numbers of α particles, and to assay for oncogenic transformation. The single-cell microbeam delivered no, one, two, four or eight α particles through the nuclei of all or just 10% of C3H 10T½ cells. We show that (a) more cells can be inactivated than were actually traversed by α particles and (b) when 10% of the cells on a dish are exposed to α particles, the resulting frequency of induced transformation is not less than that observed when every cell on the dish is exposed to the same number of α particles. These observations constitute evidence suggesting a bystander effect, i.e., that unirradiated cells are responding to damage induced in irradiated cells. This bystander effect in a biological system of relevance to carcinogenesis could have significant implications for risk estimation for low-dose radiation.

Radiation Dose-Rate: A Factor of Importance in Radiobiology and Radiotherapy

Abstract A wide range of dose-rates has been used in radiobiology or radiotherapy, extending from a few rads per day to thousands of rads in a fraction of a second. At ultra-high dose-rates (pulses of micro or nanoseconds) a clear dose-rate effect has been demonstrated for bacteria, but is less certain for mammalian cells; these doserates have no certain application in radiotherapy at the present time. The principal dose-rate effect is observed between 100 rads/minute and 10 rads/hour; the cell-killing effect of X or γ rays decreases continuously as the dose-rate decreases throughout this range, and may be explained readily in terms of the repair of sub-lethal damage taking place during the irradiation. At lower dose-rates cell proliferation continues during the irradiation, and the ultimate outcome is a complex function of cellular radiosensitivity, dose/cell cycle and tissue adaptability. In clinical radiotherapy, the traditional pattern of high dose-rate for external beam therapy and low dose-rate for ...

The radiobiology of radiosurgery: Rationale for different treatment regimes for AVMs and malignancies

Based on basic radiobiological principles, we suggest that the radiosurgery technique of delivering a radiation dose in a single fraction, whilst appropriate for benign brain lesions such as arteriovenous malformations (AVM), is not optimal for treating malignant tumors. Radiosurgery was originally developed to treat benign lesions in the brain, such as AVMs, and has been successfully used for this purpose for over four decades. Recently, the technique has been adopted for treating small primary malignant brain tumors or single metastases. We argue, and derive radio-biological data to support the view that, treating malignant tumors with a single fraction will result in a suboptimal therapeutic ratio between tumor control and late effects, even for small tumors; and that improved therapeutic ratios would be expected if the treatment were fractionated into a small number of fractions. On the other hand, no therapeutic gain is to be expected from fractionating treatment of AVMs. A new generation of noninvasive relocatable stereotactic head frames makes feasible the use of fractionated stereotactic external-beam radiotherapy, and may allow significant benefits over single, radiosurgical, treatments for malignant brain tumors. As stereotactic fractionation/protraction regimes become more widespread, a uniform approach for determining equivalent fractionation schemes becomes important for intercomparing clinical results, and such calculations can be reliably carried out using the linear-quadratic formalism.