A consistent formalism for the application of phantom and collimator scatter factors.

A coherent system for the use of scatter correction factors, determined at 10 cm depth, is described for dose calculations on the central axis of arbitrarily shaped photon beams. The system is suitable for application in both the fixed source-surface distance (SSD) and in the isocentric treatment set-up. This is in contrast to some other proposals where only one of these approaches forms the basis of the calculation system or where distinct quantities and data sets are needed. In order to derive the relations in the formalism, we introduced a separation of the phenomena related to the energy fluence in air and to the phantom scatter contribution to the dose. Both are used relative to quantities defined for the reference irradiation set-up. It is shown that dose calculations can be performed with only one set of basic beam data, obtained at a reference depth of 10 cm. These data consist for each photon beam quality of measured collimator and phantom scatter correction factors, in combination with a set of (percentage/relative) depth-dose or tissue-phantom ratio values measured along the central axis of the beam. Problems related to measurements performed at the depth of maximum absorbed dose, due to the electron contamination of the beam, are avoided in this way. Collimator scatter correction factors are obtained by using a mini-phantom, while phantom scatter correction factors are derived from measurements in a full scatter phantom in combination with the results of the mini-phantom measurements. For practical reasons the fixed SSD system was chosen to determine the data. Then, dose calculations in a fixed SSD treatment set-up itself are straightforward. Application in the isocentric treatment set-up needs simple conversion steps, while the inverse approach, from isocentric to fixed SSD, is described as well. Differences between the two approaches are discussed and the equations for the conversions are given.

A three-Gaussian fit of phantom scatter correction data.

The phantom scatter correction factor Sp of megavoltage photon beams can be accurately described using a three-Gaussian fit. The model leads to six parameters, with which Sp(r) is described as a smooth function of the field radius r for beam qualities in the range from 60Co up to 25 MV. The parameters allow Sp values to be calculated at intermediate beam energies and for any field shape. Calculated Sp(X, Y) values for rectangular fields (X, Y) can be subsequently used as reference values to compare with measured Sp(X, Y) values, for example when appraising a new beam.

Is there a need for a revised table of equivalent square fields for the determination of phantom scatter correction factors?

The use of the British Journal of Radiology (BJR) (supplement 17) tables of equivalent square fields for dose calculations is widespread. A revised version of the supplement was published recently, with a more elaborate discussion, but without changes in data given in these tables (Br. J. Radiol. suppl 25). The tables were generated for use in dose calculations, with relative beam data such as PDD, BSF, PSF, all with d(max) as the reference depth. However, the current philosophy in dose calculational methods is based on quantities defined at a reference depth, d(ref) = 10 cm, on a separation of phantom and head scatter, and on the use of the relative depth-dose or tissue-phantom ratios normalized at d(ref). By using these quantities as a starting point, problems at shallow depths related to the influence of contaminating electrons in the beam can be eliminated. Recently, a comprehensive set of phantom scatter factor data with d(ref) = 10 cm has been published for a set of square field sizes and a wide range of photon beam energies, showing that phantom scatter is a smoothly varying function of field size and quality index. It is not a priori evident that the conventional concept of equivalent squares for rectangular fields is also fully applicable for phantom scatter factors and phantom scatter related quantities at a depth of 10 cm. It was questioned whether or not new tables of equivalent square fields are needed for this purpose. In this paper, new tables have been constructed for four photon beam energies in the range of Co-60 to 25 MV (quality index from 0.572 to 0.783). The small differences between the outcome of these new tables allowed the construction of one averaged table of equivalent square fields. Phantom scatter factors were calculated for rectangular fields based on the use of the BJR table and on the use of the newly constructed tables and the differences were quantified. For Co-60 no improvements could be shown when using the new averaged table, but for beam energies of 6 to 10 MV small improvements of the order of 0.5 to 1.0% were found. For a higher beam energy of 25 MV the improvement is smaller. Deviations resulting from the BJR table are within the limits of accuracy as stated by the authors. Therefore, for clinical use, the continued use of the BJR table of equivalent squares for phantom scatter factors and phantom scatter related quantities of rectangular fields is justified, irrespective of photon beam energy.

A table of phantom scatter factors of photon beams as a function of the quality index and field size.

Phantom scatter factors, for square fields of various sizes, have been determined at a fixed reference depth of 10 cm, separately in different institutes, for a large number of linear accelerators under the auspices of the Netherlands Commission on Radiation Dosimetry. The method used for these measurements has been described in a previous paper. The present article describes the conversion of the measured values into a comprehensive and consistent data set, that gives the phantom scatter factor as a function of field size (from 4 cm up to 40 cm) and quality index (from 0.600 up to 0.800).

The determination of phantom and collimator scatter components of the output of megavoltage photon beams: measurement of the collimator scatter part with a beam-coaxial narrow cylindrical phantom.

The separation of the total scatter correction factor Sc,p in a collimator scatter component, Sc, and a phantom scatter component, Sp, has proven to be an useful concept in megavoltage photon beam dose calculations in situations which differ from the standard treatment geometry. A clinically applicable method to determine Sc is described. Measurements are carried out with an ionization chamber, placed at a depth beyond the range of contaminant electrons, in a narrow cylindrical polystyrene phantom with a diameter of 4 cm of which the axis coincides with the beam axis. Sc,p is measured in a full-scatter phantom and Sp can be derived from Sc,p and Sc. In order to obtain a reliable separation, i.e. excluding the influence of contaminant electrons, measurements of Sc,p have been carried out at depths of 5 cm for photon beams with a quality index (QI) up to and including 0.75 and a depth of 10 cm with QI larger than 0.75. These depths are in accordance with recommendations given in recent dosimetry protocols. The consistency of the method was checked by comparing calculated and measured values of Sc,p for a set of blocked fields for a range of photon beam energies from 60Co up to 25 MV showing a maximum deviation of 2%. The method can easily be implemented in existing procedures for the calculation of the number of monitor units to deliver a specified dose to a target volume.

Oxygen tensions in two human tumor cell lines grown and irradiated as multicellular spheroids.

Cells from two human cell lines were irradiated both as multicellular tumor spheroids (MTS) and in monolayer culture. Radiation response of MTS was quantified in terms of specific growth delay and proportion cured, and as clonogenic cell survival for monolayer cells. Radiation was applied either as a single or as a split dose with time intervals of 1, 2, and 4 h to determine the rate of sublethal damage repair. Using as endpoint the fraction of MTS cured at an iso-effect level, in MTS of NB-100 neuroblastoma cells repair of sublethal damage was complete within 1 h, whereas in MTS of HN-1 squamous cell carcinoma cells there was still some unrepaired damage left. At a larger dose for NB-100 MTS the repair curve showed a similar shape as for HN-1 spheroids. Using as endpoint specific growth delay, no difference in repair between the various time intervals was observed. In monolayer cells from both cell lines sublethal damage was not fully repaired in the time intervals used. Polarographic microelectrode measurements of oxygen tension inside MTS showed a marked difference in steepness of oxygen tension profiles between MTS from both cell lines. In HN-1 squamous cell carcinoma MTS with diameters up to 500 microns the central pO2 amounted to about 100 Torr, whereas in NB-100 neuroblastoma MTS with the same diameters central pO2-values lower than 30 Torr were observed. NB-100 MTS were irradiated with doses of 5 and 10 Gy gamma rays and subsequently the oxygen tension was measured 1 and 5 h after irradiation. A reoxygenation effect could not be observed, either after single dose or after split dose irradiation. If spheroids may be regarded as a suitable model for tumor responses in vivo, the results from these experiments indicate that reoxygenation is a process eluding polarographic measurements, or that no dramatic changes in oxygen tension are to be expected shortly after high single doses or early in a fractionation scheme.

Repair of radiation induced damage in two human tumour cell lines grown as spheroids and monolayers.

Growth curves of two human tumour cell lines grown as multicellular tumour spheroid (MTS) were used to obtain survival estimates by back-extrapolation after split and single dose irradiation. Neuroblastoma (NB-100) and squamous cell carcinoma (HN-1) single cells from monolayer culture were assessed for repair of sublethal and potentially lethal damage. The extent of repair was calculated on an iso-effect basis. When grown as spheroids squamous cell carcinoma cells showed a higher capacity to repair sublethal damage than neuroblastoma cells. Repair of potentially lethal damage did not contribute to this higher capacity of HN-1 cells, since this cell line was found to be deficient for this type of repair. Using the recovery ratio to estimate the beta-component of the survival curves, it was found that differences in repair capacity were determined by the alpha-component of the equation. Our results show the feasibility of back-extrapolating multicellular tumour spheroid growth curves to obtain survival estimates that can be applied to establish sublethal damage repair capacity.

Clinical and physical aspects of total body irradiation for bone marrow transplantation in Nijmegen.

Eighty-nine patients were transplanted with allogeneic bone marrow after a standard conditioning regimen consisting of cyclophosphamide and fractionated total body irradiation (2 x 4.5 Gy) with average dose rates of 4.1 and 12.3 cGy/min, respectively. The average rectum and lung dose was 9.2 +/- 0.45 and 7.5 +/- 0.78 Gy. In vivo dosimetry was performed in 71 patients irradiated with 18 MV X-rays from left and right lateral. Forty-three patients (48%) died. After increasing the dose rate the incidence of interstitial pneumonitis increased, but the number of relapses decreased.

Radiosensitivity of different human tumor cells lines grown as multicellular spheroids determined from growth curves and survival data.

Five human tumor cell lines were grown as multicellular tumor spheroids (MTS) to determine whether multicellular tumor spheroids derived from different types of tumors would show tumor-type dependent differences in response to single-dose irradiation, and whether these differences paralleled clinical behavior. Multicellular tumor spheroids of two neuroblastoma, one lung adenocarcinoma, one melanoma, and a squamous cell carcinoma of the oral tongue, were studied in terms of growth delay, calculated cell survival, and spheroid control dose50 (SCD50). Growth delay and cell survival analysis for the tumor cell lines showed sensitivities that correlated well with clinical behavior of the tumor types of origin. Similar to other studies on melanoma multicellular tumor spheroids our spheroid control dose50 results for the melanoma cell line deviated from the general pattern of sensitivity. This might be due to the location of surviving cells, which prohibits proliferation of surviving cells and hence growth of melanoma multicellular tumor spheroids. This study demonstrates that radiosensitivity of human tumor cell lines can be evaluated in terms of growth delay, calculated cell survival, and spheroid control dose50 when grown as multicellular tumor spheroids. The sensitivity established from these evaluations parallels clinical behavior, thus offering a unique tool for the in vitro analysis of human tumor radiosensitivity.

Repair of sublethal damage in two human tumor cell lines grown as multicellular spheroids.

Multicellular tumor spheroids (MTS) provide a suitable in vitro model to study radiation sensitivity of tumor cells. Two cell lines of human origin, obtained from a neuroblastoma (NB-100) and a squamous cell carcinoma (HN-1), were exposed to graded doses (4-9 Gy) of radiation with 18 MV photons. Radiation was applied either as a single or as a split dose with an interval of 6 hr to determine the extent of sublethal damage repair. Treated spheroids regrew at approximately the same growth rate as control multicellular tumor spheroids, preceded by a static or regression phase. Radiation response was quantified in terms of regrowth delay, expressed as the time needed for treated spheroids to obtain an 8-fold increase of the initial volume at the time of irradiation. Data obtained from regrowth delay analysis were used to calculate the extent of sublethal damage repair, showing for the squamous cell carcinoma line a fractionally higher capacity to repair sublethal damage than the neuroblastoma line. Repair increased with larger dose fractions in both cell lines. Our results show that multicellular tumor spheroids from the two cell lines used in this study are best applicable at relatively high total radiation doses. This makes multicellular tumor spheroids a suitable model for the in vitro evaluation of clinical treatment rationales such as hyperfractionation.

Radiotherapy of choroidal metastases.

With binocular indirect ophthalmoscopy, fluorescin angiography and ultrasonography 68 choroidal metastases in 52 eyes of 39 patients were diagnosed. The primary tumors were mainly breast cancer (81%) and lung cancer (10%). After radiation treatment the visual acuity improved in 17 eyes (38%), stabilized in 15 eyes (33%), whereas in 13 eyes (29%) deterioration could not be prevented (seven eyes unknown). Regression of the lesions or its accompanying secondary retinal detachment was seen in 78% of the eyes treated. Acute transient side effects of radiation therapy were kerato-conjunctivitis (nine patients) and acute glaucoma in one patient. No cataractous changes of the lens were observed in the post radiation period (one to 42 months). Irradiation of choroidal metastases can contribute to improvement of the quality of life with a treatment scheme of 30 Gy in ten daily fractions.

Development and applications of an animal model for human tumor xenografts.

Wistar rats treated with cyclophosphamide (4x 10 mg/kg), total lymphoid irradiation (9.0 Gy; dose rate 0.60 Gy/min) and cyclosporin A (15 mg/kg, daily, orally) developed a state of immune suppression permitting the growth of human tumor xenografts. Immunosuppression was monitored by lymphocyte counts, serum IgG determination. PHA and Con A lymphocyte-responses, proportion of B cells and histopathological studies of the lymphoid organs. The lymphocyte counts, IgG levels, PHA and Con A stimulation values remained severely depressed, during the period of cyclosporin A administration. Repopulation of the paracortical areas of the lymph nodes and the peri-arteriolar sheaths of the spleen did not occur, neither the reconstruction of the germinal centers in these organs. The thymus underwent severe atrophy. Seven of eight different types of human tumors were successfully xenografted in the immunomodified rat. The xenografted tumors maintained their original morphologic features and the mitotic rate did not change during subsequent transplantations.