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A purpose-built iodine-125 irradiation plaque for low dose rate low energy irradiation of cell lines in vitro

¹ Medical Physics Department, Mount Vernon Hospital, Northwood, Middlesex, HA6 2RN ² Gray Laboratory Cancer Research Trust, PO Box 100, Mount Vernon Hospital, Northwood, Middlesex, HA6 2JR, UK

	Abstract

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

 
The phenomenon of hyper-radiosensitivity (HRS) to very low acute single doses of radiation has been demonstrated in several cell lines in vitro and in vivo, and has been studied in theory and in practice. The theory suggests a similar hypersensitivity when cells are continuously exposed to radiation at very low dose rates. These low dose rates are used when radioactive seed (iodine-125 or palladium-103) implants of the prostate are used as an alternative to surgery or external beam radiotherapy. To investigate the radiobiology of hypersensitivity of this type on various cell lines in vitro, an iodine-125 seed irradiator has been designed and built for safe use in the Gray Laboratory. In practice, the calculated dose rate has been used for consistency. Discrepancies between calculated and measured dose rates are discussed.

	Introduction

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

 
The phenomenon of hyper-radiosensitivity (HRS) to very low acute single doses of radiation has been demonstrated in several cell lines in vitro [1–9] and in vivo [10]. HRS produces lower cell survival at doses less than 1 Gy compared with the prediction of the linear quadratic (LQ) model, which is based on extrapolation from higher doses. The effect is more apparent in radioresistant cell lines. It has been proposed that HRS reflects a differential triggering or induction of repair mechanisms, so that at very low doses below a certain threshold, DNA repair mechanisms are not triggered and cells remain sensitive. Following increased levels of damage that occur at higher doses (typically above 0.7 Gy), cells induce or trigger repair mechanisms and therefore exhibit increased radioresistance. A modification of the LQ equation, termed the "induced repair" (IR) equation, has been introduced to model the survival of cell lines that behave in this way.

The IR equation predicts that this hypersensitivity to radiation at low acute doses would translate into a similar sensitivity when cells are exposed continuously to radiation at a very low dose rate. As with low acute single doses of radiation, cells continuously exposed to low dose rate irradiation will be receiving very small amounts of radiation per unit time and it is proposed that insufficient sudden damage will be caused to induce activation of repair mechanisms within the cell. It is possible that very low dose rates of continuous irradiation may be even more effective at cell killing than acute low doses, since a greater total dose can be given. Several previous studies have demonstrated an inverse dose rate effect on mutation induction at very low dose rates, with lower dose rates causing greater mutation than higher dose rates [11–14]. A recent report has indicated that low dose rate X-rays induce larger deletions at the human HPRT gene than high dose rates [15].

Development of radioactive RAPID STRAND iodine-125 "seeds" by Nycomed Amersham (Amersham, UK) has offered an alternative to surgery and external beam radiotherapy in the treatment of some cancers. These seeds are expected to be of benefit in tumours that are more resistant to other types of cancer therapy, such as tumours in the prostate and the pancreas [16], since they offer an effective means of increasing locally applied dose whilst sparing surrounding tissues. Implantation time takes 1–2 h, with day surgery and an overnight stay. Subsequent urinary incontinence or impotence, which are common side effects with surgery or external beam radiotherapy in prostate cancer treatment, are rare. The seeds contain the radioisotopes iodine-125 (half-life t_1/2=59.4 days) or palladium-103 (t_1/2=17 days) and are designed for insertion directly into the tumour where they emit gamma radiation over a protracted period of time. However, it is not known exactly how the continuous dose of radiation affects tumour cell survival. In some situations, the seeds appear to be more effective than predicted from the delivered dose [17]. It is possible that this is because the tumour cells are showing hypersensitivity to the low dose rate exposure from the implanted seeds.

This paper describes the development of a purpose-built iodine-125 seed irradiator to investigate the effect of low dose rate radiation exposure on the survival of cell lines in vitro.

	Iodine-125

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

 
The radionuclide iodine-125 has been used in the form of small sealed radiation sources (seeds) for many years. The seeds have been used since the early 1970s for treatment of prostate cancer [17]. Since that time, implantation techniques and the accuracy of dosimetry have improved. Large numbers of implants are now performed in North America and the technique is beginning to be used extensively in the UK.

Two types of seed are available from Amersham International. The lower activity Code IMC6711 seeds (air kerma rate (AKR) 0.24–7.92 µGy h^-1, or equivalent activity 0.28–1.04 mCi) are used for permanent implantation of the prostate. They consist of a welded titanium capsule containing iodine-125 adsorbed onto a silver rod. The higher activity Code IMC6702 seeds (AKR 6.4–50.8 µGy h^-1, equivalent activity 5.0–40.0 mCi) consist of a welded titanium capsule containing iodine-125 adsorbed onto an ion exchange resin sphere. These are commonly used for treatment of brain tumours using temporary stereotactic interstitial implantation.

Although the lower activity IMC6711 RAPID STRAND seeds are usually used for prostate treatment, it is the higher activity IMC6702 seeds that are used in the work described in this paper. With the plaque design described below, it is possible using the high activity seeds to begin experiments at a dose rate of about 40 cGy h^-1 and allow decay to take the dose rate down to less than 5 cGy h^-1 (used in prostate treatment) in a period of about 180 days. The typical initial dose rate for prostate treatment is about 7 cGy h^-1, giving a total dose of 145 Gy at full decay.

The physical characteristics (Table 1) of the two types of seed are very similar. The main differences are a slightly different anisotropy and spectrum of radiation. These differences were not considered significant for the biological experiments undertaken with the plaque.

	Dosimetry of iodine-125

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

Details of the American Association of Physicists in Medicine (AAPM) formalism will not be given here. Only the final formula of dose rate that has been used in this work will be given to illustrate the complex factors involved.

The dose rate DR at point (r,) is given by:

where S_k is the air kerma strength of the source (µGy m² h^-1); A is the dose rate constant for iodine-125 (a factor that transforms air kerma strength to dose rate (cGy h^-1) in water based on measurements); G(r,) is the geometry factor, which accounts for the variation of relative dose owing to only the spatial distribution of activity within the source; G(r₀,₀) is the geometry factor for r₀=1 cm and ₀=/2; g(r) is the radial dose function, which accounts for the effects of absorption and scatter in the medium along the transverse axis of the source; and F(r,) is the anisotropy function, which accounts for the anisotropy of dose distribution around the source, including the effects of absorption and scatter in the medium.

Considerations for the design of a mould
Moulds were used extensively in early brachytherapy using radium-226 and sometimes gold-198 sources. The dosimetry rationale for these sources has been described by Meredith [19]. The original physics treated the radioactivity as small discrete sources or, for circular applications, as a continuous circular source train.

No corrections were made for any of the factors that are now in the modern AAPM formalism. In fact, apart from the attenuation in the source and wall, this approximation is justified in the original work since both the radial function and the anisotropy factor for radium-226 or gold-198 are small.

The principles of the "Manchester System" mould [19] have been applied in this work in order to have a starting point for the design of an iodine-125 applicator. The dosimetry of the final design was then studied using an adaptation of the AAPM formalism to check that the design was satisfactory.

In the language of the Manchester System, the mould chosen for this work is planar with the radioactivity distributed in circles. The distribution of the radioactivity depends on D/h, the ratio of the diameter D of the mould to the treatment distance h, where the treatment distance h is the distance between the source plane and the treatment plane. To achieve optimum uniformity across the treatment plane, the following rules apply: for D/h<3, a single circle of sources is sufficient; for 3<D/h<6, 5% of the radioactivity should be placed at the centre; for larger values of D/h, two concentric circles and a centre spot should be used.

For the dimensions of the plaque used in this work (D=3 cm, h=0.6 cm) D/h=5, so a single circle with a centre spot was used.

As many sources as possible should be used in the circle, but it has been shown that a smaller number of sources can be used provided that a space, not exceeding the treatment distance h, exists between the active ends of adjacent sources. This requirement was not quite achieved in the final design owing to the limited availability of seeds and the desire to have several plaques available for experiments at once.

With the design described above, variation of dose rate (for a radium source) across the surface of the treated area should be no greater than ±5%; with iodine-125 this variation may be ±10%.

The final design
The arrangement for using the plaques is shown in Figure 1a. The plaque itself (Figure 1b) consists of nine seeds, confined within a 50 mm diameter cylindrical assembly fabricated from cross-linked polystyrene, which was chosen for its approximate tissue equivalence (for iodine-125 radiation) and its very high resistance to radiation damage. Eight seeds are equally spaced within recesses around the circumference of a 30 mm diameterx1 mm thick polystyrene disc. A ninth seed is confined to the centre within a 6 mm diameter hole. The disc and the seeds are "sandwiched" between two other pieces of polystyrene such that the seeds are secure and constrained from moving. The polystyrene layer above the seeds is 6 mm thick and is designed to support the cell dish. A threaded hole in the base of the polystyrene assembly allows it to be secured to the base of a 116 mm diameterx80 mm high steel cylindrical container, with a steel and lead lid. For the experiments described here, five irradiators of similar design have been constructed.

View larger version (22K): [in this window] [in a new window]   Figure 1. (a) Complete assembly showing cell dish on top of plaque inside protected container. The cells to be irradiated form a layer on the surface of the dish at a fixed distance from the plaque; the liquid level indicated in the drawing is that of fluid used to keep the cells sustained during irradiation. (b) Arrangement of nine seeds on the plaque.

For the seeds loaded into the first plaque, the following calculations were made (an adaptation of TG(43) [18]):

with the geometry factor taken as 1/r², assuming a point source for this factor.

The set of seeds used on the first plaque had the following equivalent activities: central seed, 6.5 mCi; peripheral seeds, 8x7.9 mCi. For subsequent plaques the central seed had the same activity as the peripheral seeds, taking A=0.93 cGy h^-1 U^-1 and 1 mCi=1.27 U.

The dose rates at various points on the treatment plane (at 6 mm above the seed plane) are given in Table 2. The isodose distribution is shown in Figure 2. The actual maximum/minimum dose rate ratio was 1.54. To reduce this ratio it was decided to rotate the plaque (or, in practice, the cell dish) by 22.5° for half the exposure time. The maximum/minimum total dose rate ratio then becomes 1.23. If the hot spot above the central seed is ignored, a mean dose rate can be taken as 39.69 cGy h^-1. If the hot spot above the central seed is ignored and the plaque is rotated 22.5° for half the exposure time, the mean dose rate is 39.75 cGy h^-1.

View larger version (49K): [in this window] [in a new window]   Figure 2. Isodose distribution showing percentage levels with respect to mean dose rate used for the first plaque (scale in cm).

where t is time (h), is the decay constant for ¹²⁵I and T is the length of irradiation (h). For these calculations, T_1/2=1425.6 h (59.4 days).

Alternatively, if it is wished to give 50 Gy at this initial dose rate then the length of irradiation T must be given from:

so that T=129.8 h.

	Plaque measurements

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

 
After loading the plaque, the distribution of seeds was checked using autoradiography. It is also possible to do this check on a gamma camera using a pinhole collimator.

To verify the dose rate at 6 mm from the seed plane, various dosimetric methods were considered. There are several difficulties with this radiation field: (i) dimensions both laterally and in depth of the sensitive volume are required; (ii) low energy of the photons; and (iii) low dose rate.

Disc-type ion chambers were considered but rejected on the grounds of lack of sensitivity and the high level of energy dependence in this energy range. Film was useful to check the distribution of sources, but was not an accurate dosemeter. Thus, thermoluminescent dosemeters (TLDs) remained the only option. A batch of high sensitivity TLDs (LiF crystals doped with Mg, Cu and P [20]) for which the energy sensitivity is reasonably low (±10% for 10–1000 keV; see discussion regarding errors) was used. These were calibrated using a superficial energy X-ray tube with filtration and tube potential (kVp) to produce an average energy close to that of iodine-125 photons. The characteristics of this X-ray beam were: 70 kVp with 1.25 mm Al filter added; first half-value layer 1.4 mm Al; estimated effective photon energy 31 keV; focus-to-surface distance 30 cm; and field size 8 cm. This was calibrated using an ionization chamber traceable to standard at NPL, with IPEM Code of Practice [21]. This is not ideal and may be the main cause of the systematic discrepancy in measured dose (see below) compared with calculated dose. Nine dosemeters were placed in a square array over the plaque. To deal with hot spots over seeds (except for the central seed), the plaque was rotated by 22.5° (half the angle between peripheral seeds) mid way through an exposure. The average of all TLD readings was then taken to represent the average dose across the plaque in the treatment plane.

The results are given in Table 3 for four different plaques, all with the same design but slightly different nominal activities.

	Errors

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

• The mean activity from the supplier's certificate was used, which is subject to an uncertainty of ±5%. This has been interpreted to mean that all the activities within a stated batch fall within this range. However, it would be possible, by chance, to load an individual plaque with a set of seeds with a biased activity.
  
• Uncertainty in the scatter contribution at the surface of the plaque. In TG(43), g(r) is based on full scatter contribution, whereas in these experiments only partial scatter is present.
  

The measured doses are subject to measurement errors and systematic errors.

Measurement errors:

• Individual TLD chip calibration of about ±5% (1 SD).
  
• Position of TLDs with respect to seeds ±7%.
  

Systematic errors:

• Uncertainty in calibration factor ±7% (1 SD).
  
• Uncertainty in scatter contribution.
  

	Containment/radiation protection (Figure 1a)

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

 
The plaques were attached with screws to a metal base, which was then surrounded with a steel cylinder. Containment was completed with a steel and lead lid. The complete vessel could then be used safely without the need to use any further radiation protective shielding since a negligible dose rate was evident, even close to the container.

	Discussion and conclusion

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

 
This plaque design is very efficient and effective and has already been used extensively in radiobiological experiments. However, modifications could be made to improve the uniformity of dose, caused by a combination of too few seeds and the attenuation factor, by introducing more seeds in the outer circle and by using a small inner circle instead of a central source.

It is extremely difficult to verify calculated doses for this quality of radiation at very low dose rate. Random errors introduce an uncertainty of about ±8.6%. The main systematic errors are most likely calibration of the TLDs and lack of scatter at the surface of the plaque. Given these uncertainties, it seems appropriate to use calculated doses based on TG(43) for this and future radiobiological work with iodine-125.

Received for publication March 27, 2000. Revision received July 14, 2000. Accepted for publication August 7, 2000.

	References

Top Abstract Introduction Iodine-125 Dosimetry of iodine-125 Plaque measurements Errors Containment/radiation protection... Discussion and conclusion References

 

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