METHODS

To measure dose enhancement in aqueous iodinated solutions, we resorted to ferrous sulphate dosimetry. The main problem of absorbed dose quantification in the presence of DEAs is the short range of secondary radiation (from a few nanometers for Auger electrons to a few micrometers for photoelectrons and characteristic X-rays), which imposes certain limitations on the use of conventional dosimetry techniques. Here, liquid ferrous sulphate dosimetry offers a solution. This technique employs oxidation of Fe²⁺ to Fe³⁺ by highly reactive products of water radiolysis induced by ionizing radiation. The number of yielded Fe³⁺ ions depends on the absorbed radiation dose and therefore allows to calculate the exact value of the latter. The dosimeter solution can be “supplemented” with DEA; thus Fe³⁺ ions will be in close proximity to DEA atoms, and the effect of secondary radiation on the total absorbed dose can be estimated.

In our experiment dose enhancement was attempted with iodine (Ultravist 370, a iodine-based contrasting agent by Bayer, Germany), whose atomic number is 53. Iodine concentrations of 2.5, 5, 10, 20 and 50 mg/ml were created in the solutions of ferrous sulphate dosimeters. The solutions were prepared as described in [19].

Spectrophotometric measurements of absorbance at the peak of light absorption by Fe³⁺ ions are performed at 303 nm wavelength. The optical absorption spectrum of iopromide interferes with that of iron; therefore, we modified the dosimeter by adding ammonium rhodanide (thiocyanate) NH₄SCN. Once ferric ions reacted with rhodanide, a intensely colored orangish-red Fe³⁺/thiocyanate complex was formed with the absorption peak at 460 nm. We added 100 μl of 0.1 g/ml ammonium rhodanide solution to every irradiated iodinated dosimeter solution and then measured the absorption spectrum and absorbance for the Fe³⁺/thiocyanate complex using Cary 50 spectrophotometer (Varian Australia Pty, Australia).

An increase in the absorbed dose can be expressed using a dose enhancement factor (DEF): DEF = D_contrast/D, where D_contrast is the dose absorbed by the irradiated dosimeter containing a dose-enhancing agent, as measured by spectrophotometry, and D is the absorbed dose in the absence of DEA. The absorbed dose was calculated based on the calibration curve for doses ranging from 2.5 to 20 Gy.

In our experiment we used the 6 MV clinical electron accelerator SL75-5-MT (Efremov Research Institute of Electrophysical Equipment, Russia) from the radiation therapy unit of Blokhin Russian Cancer Research Center. The accelerator generates bremsstrahlung radiation with photon energies up to 6 MeV. Prior to irradiation, the dosimeter solutions were placed in 40 mm Petri dishes, 2.5 ml of solution per dish. Irradiation time was 100 seconds, which is sufficient for iodine-free water to absorb 5 Gy. No tissue equivalent scatterers were used in this study, because its aim was to model conditions for surface irradiation, typical for in vitro and in vivo studies (in mice and rats with transplanted tumors).

Spectrophotometric measurements were done in 6 repeats for each DEA concentration. The mean absorbed dose and the standard error of the mean were calculated for each concentration considering Student’s coefficient. Statistical significance was estimated by the Mann–Whitney U-test.

RESULTS

The calibration curve in fig. 2 shows that absorbance of the ferrous sulphate dosimeter is linearly dependent on the absorbed dose (doses range from 2.5 to 20 Gy).

Mean values of the dose enhancement factor for each studied iodine concentration are shown in the table. A 13 % dose enhancement was observed at a concentration of 50 mg/ml. For other studied concentrations DEF was < 1.

DISCUSSION

The obtained results show that typical concentrations of DEA accumulated in the tumor (2–50 mg/ml) do not have any clinically significant effect on the radiation dose absorbed during CERT with 6 MV photons. Absorbed dose enhancement does not exceed the uncertainty value at iodine concentrations ≤ 20 mg/ml. Significant dose enhancement (by 13 ± 5 %) was observed at a 50 mg/ml iodine concentration. The results of our study are consistent with the findings of other authors [17, 18]. It should be noted that iodine concentrations > 20 mg/ml can be reached only by direct injections of DEA into the tumor, which is strongly disapproved of by the medical community. Systemically administered DEAs usually have iodine concentrations ranging between 2 and 15 mg/ml [2, 20]. To sum up, no clinically significant dose enhancement was registered in the solutions irradiated with 6 MV photons at typically used iodine concentrations, which means that no improved therapeutic effect should be expected.

CONCLUSIONS

Our findings suggest that standard sources of 6 MV energies used in clinical routine cannot ensure clinically significant enhancement of the absorbed dose for contrast-enhanced radiotherapy. The antitumor effect of 6 MV photons in the presence of dose-enhancing agents in the tumor is likely to be a case of radiosensitization and is not caused by increased absorption of radiation by the tumor. A question remains whether the use of flattening filters for orthovoltage and kilovoltage energies can be avoided during 6 MV CERT.