Factors for converting dose measured in polystyrene phantoms to dose reported in water phantoms for incident proton beams.

PURPOSE: Previous dosimetry protocols allowed calibrations of proton beamline dose monitors to be performed in plastic phantoms. Nevertheless, dose determinations were referenced to absorbed dose-to-muscle or absorbed dose-to-water. The IAEA Code of Practice TRS 398 recommended that dose calibrations be performed with ionization chambers only in water phantoms because plastic-to-water dose conversion factors were not available with sufficient accuracy at the time of its writing. These factors are necessary, however, to evaluate the difference in doses delivered to patients if switching from calibration in plastic to a protocol that only allows calibration in water. METHODS: This work measured polystyrene-to-water dose conversion factors for this purpose. Uncertainties in the results due to temperature, geometry, and chamber effects were minimized by using special experimental set-up procedures. The measurements were validated by Monte Carlo simulations. RESULTS: At the peak of non-range-modulated beams, measured polystyrene-to-water factors ranged from 1.015 to 1.024 for beams with ranges from 36 to 315 mm. For beams with the same ranges and medium sized modulations, the factors ranged from 1.005 to 1.019. The measured results were used to generate tables of polystyrene-to-water dose conversion factors. CONCLUSIONS: The dose conversion factors can be used at clinical proton facilities to support beamline and patient specific dose per monitor unit calibrations performed in polystyrene phantoms.

Dose response of CaF2:Tm to charged particles of different LET.

Thermoluminescent dosimeters are well established for performing calibrations in radiotherapy and for monitoring dose to personnel exposed to low linear energy transfer (LET) ionizing radiation. Patients undergoing light ion therapy and astronauts engaged in space flight are, however, exposed to radiation fields consisting of a mix of low- and high-LET charged particles. In this study, glow curves from CaF2:Tm chips were examined after exposure to various electron and ion beams. The annealing and readout procedures for these chips were optimized for these beams. After a 10 min prereadout annealing at 100 degrees C, the optimized glow curve samples the light output between 95 and 335 degrees C with a heating rate of 2 degrees C/s. The ratio of the integral of the glow curve under peaks 4-6 to the integral under peak 3 was approximately 0.9 for electrons, 1.0 for entrance protons, 1.6 for peak protons, and 2.2 for entrance carbon, silicon, and iron ions. The integral light output per unit dose in water for the iron exposures was about half as much as for the electron exposures. The peak-area-ratio can be used to determine a dose response factor for different LET radiations.

Spill-to-spill and daily proton energy consistency with a new accelerator control system.

The Loma Linda University proton accelerator has had several upgrades installed including synchrotron dipole power supplies and a system for monitoring the beam energy. The consistency of the energy from spill-to-spill has been tested by measuring the depth ionization at the distal edge as a function of time. These measurements were made with a minimally equipped beamline to reduce interference from confounding factors. The consistency of the energy over several months was measured in a treatment room beamline using an ionization chamber based daily quality assurance device. The results showed that the energy of protons delivered from the accelerator (in terms of water equivalent range) was consistent from spill-to-spill to better than +/-0.03 mm at 70, 155, and 250 MeV and that the energy check performed each day in the treatment room over a several month period was within +/-0.11 mm (+/-0.06 MeV) at 149 MeV. These results are within the tolerances required for the energy stacking technique.

Leakage and scatter radiation from a double scattering based proton beamline.

Proton beams offer several advantages over conventional radiation techniques for treating cancer and other diseases. These advantages might be negated if the leakage and scatter radiation from the beamline and patient are too large. Although the leakage and scatter radiation for the double scattering proton beamlines at the Loma Linda University Proton Treatment Facility were measured during the acceptance testing that occurred in the early 1990s, recent discussions in the radiotherapy community have prompted a reinvestigation of this contribution to the dose equivalent a patient receives. The dose and dose equivalent delivered to a large phantom patient outside a primary proton field were determined using five methods: simulations using Monte Carlo calculations, measurements with silver halide film, measurements with ionization chambers, measurements with rem meters, and measurements with CR-39 plastic nuclear track detectors. The Monte Carlo dose distribution was calculated in a coronal plane through the simulated patient that coincided with the central axis of the beam. Measurements with the ionization chambers, rem meters, and plastic nuclear track detectors were made at multiple locations within the same coronal plane. Measurements with the film were done in a plane perpendicular to the central axis of the beam and coincident with the surface of the phantom patient. In general, agreement between the five methods was good, but there were some differences. Measurements and simulations also tended to be in agreement with the original acceptance testing measurements and results from similar facilities published in the literature. Simulations illustrated that most of the neutrons entering the patient are produced in the final patient-specific aperture and precollimator just upstream of the aperture, not in the scattering system. These new results confirm that the dose equivalents received by patients outside the primary proton field from primary particles that leak through the nozzle are below the accepted standards for x-ray and electron beams. The total dose equivalent outside of the field is similar to that received by patients undergoing treatments with intensity modulated x-ray therapy. At the center of a patient for a whole course of treatment, the dose equivalent is comparable to that delivered by a single whole-body XCT scan.

EDR-2 film response to charged particles.

A useful tool for verifying segmental or dynamic treatments with multiple multi-leaf collimator positions, spinning range modulator propellors or magnetically scanned beams would be a film with a linear dose response up to several hundred centiGray, as typical for delivered treatments. Kodak has released an extended range film (EDR-2) that may satisfy this desire. In this study, dose response curves were obtained for several electron, proton, carbon ion and iron ion beams of different energies to determine the utility of this film.

Calibration of a proton beam energy monitor.

Delivery of therapeutic proton beams requires an absolute energy accuracy of +/-0.64 to 0.27 MeV for patch fields and a relative energy accuracy of +/-0.10 to 0.25 MeV for tailoring the depth dose distribution using the energy stacking technique. Achromatic switchyard tunes, which lead to better stability of the beam incident onto the patient, unfortunately limit the ability of switchyard magnet tesla meters to verify the correct beam energy within the tolerances listed above. A new monitor to measure the proton energy before each pulse is transported through the switchyard has been installed into a proton synchrotron. The purpose of this monitor is to correct and/or inhibit beam delivery when the measured beam energy is outside of the tolerances for treatment. The monitor calculates the beam energy using data from two frequency and eight beam position monitors that measure the revolution frequency of the proton bunches and the effective offset of the orbit from the nominal radius of the synchrotron. The new energy monitor has been calibrated by measuring the range of the beam through water and comparing with published range-energy tables for various energies. A relationship between depth dose curves and range-energy tables was first determined using Monte Carlo simulations of particle transport and energy deposition. To reduce the uncertainties associated with typical scanning water phantoms, a new technique was devised in which the beam energy was scanned while fixed thickness water tanks were sandwiched between two fixed parallel plate ionization chambers. Using a multitude of tank sizes, several energies were tested to determine the nominal accelerator orbit radius. After calibration, the energy reported by the control system matched the energy derived by range measurements to better than 0.72 MeV for all nine energies tested between 40 and 255 MeV with an average difference of -0.33 MeV. A study of different combinations of revolution frequency and radial offsets to test the envelope of algorithm accuracy demonstrated a relative accuracy of +/-0.11 MeV for small energy changes between 126 and 250 MeV. These new measurements may serve as a data set for benchmarking range-energy relationships.

Generation and characterization of a proton microbeam for experimental radiosurgery.

A proton microbeam has been developed to support various research endeavors. Test subjects may be irradiated from any angle with respect to the vertical because the beamline is contained within a rotating gantry used for human patients. Converting from the treatment to experimental arrangement is quick and straightforward as is the reverse. Using a series of collimators, the final beam diameter at the surface of the subject is 1 mm. The depth from the surface to the Bragg peak in water is 15 mm. Fluence distributions perpendicular to the beam axis were determined by scanning radiographic film exposed at various depths with a scanner having a pixel size of 84.7 microm. The depth dose integrated over the beam area was measured using a parallel plate ionization chamber. Central axis depth doses were calculated by multiplying the ionization chamber signal by the ratio of film doses for the central axis pixels to the integrated beam doses at each depth. A Faraday cup was used to confirm the dose at the surface while TLDs, diodes, and film were used to verify the dose at depth. The usefulness of this beamline for experimental situations has been demonstrated in a feline neurological study. The dosimetry techniques are useful for narrow beams such as used for functional radiosurgery treatments of humans.

Studies of physiology and the morphology of the cat LGN following proton irradiation.

PURPOSE: We have examined the effects of proton irradiation on the histologic and receptive field properties of thalamic relay cells in the cat visual system. The cat lateral geniculate nucleus (LGN) is a large structure with well-defined anatomical boundaries, and well-described afferent, efferent, and receptive field properties. METHODS AND MATERIALS: A 1.0-mm proton microbeam was used on the cat LGN to determine short-term (3 months) and long-term (9 months) receptive field effects of irradiation on LGN relay cells. The doses used were 16-, 40-, and 60-gray (Gy). RESULTS: Following irradiation, abnormalities in receptive field organization were found in 40- and 60-Gy short-term animals, and in all of the long-term animals. The abnormalities included "silent" areas of the LGN where a visual response could not be evoked and other regions that had unusually large or small compound receptive fields. Histologic analysis failed to identify cellular necrosis or vascular damage in the irradiated LGN, but revealed a disruption in retinal afferents to areas of the LGN. CONCLUSIONS: These results indicate that microbeam proton irradiation can disrupt cellular function in the absence of obvious cellular necrosis. Moreover, the area and extent of this disruption increased with time, having larger affect with longer post-irradiation periods.

Methodologies and tools for proton beam design for lung tumors.

PURPOSE: Proton beams can potentially increase the dose delivered to lung tumors without increasing the dose to critical normal tissues because protons can be stopped before encountering the normal tissues. This potential can only be realized if tissue motion and planning uncertainties are correctly included during planning. This study evaluated several planning strategies to determine which method best provides adequate tumor coverage, minimal normal tissue irradiation, and simplicity of use. METHODS AND MATERIALS: Proton beam treatment plans were generated using one or more of three different planning strategies. These strategies included designing apertures and boluses to the PTV, apertures to the PTV and boluses to the CTV, and aperture and bolus to the CTV. RESULTS: The planning target volume as specified in ICRU Report 50 can be used only to design the lateral margins of beams, because the distal and proximal margins resulting from CT number uncertainty, beam range uncertainty, tissue motions, and setup uncertainties, are different than the lateral margins resulting from these same factors. The best strategy for target coverage with the planning tools available overirradiated some normal tissues unnecessarily. The available tools also made the planning of lung tumors difficult. CONCLUSIONS: This study demonstrated that inclusion of target motion and setup uncertainties into a plan should be performed in the beam design step instead of creating new targets. New computerized treatment planning system tools suggested by this study will ease planning, facilitate abandonment of the PTV concept, improve conformance of the dose distribution to the target, and improve conformal avoidance of critical normal tissues.

Phase I/II study of proton beam irradiation for the treatment of subfoveal choroidal neovascularization in age-related macular degeneration: treatment techniques and preliminary results.

PURPOSE: Age-related macular degeneration is the prevalent etiology of subfoveal choroidal neovascularization (CNV). The only effective treatment is laser photocoagulation, which is associated with decreased visual acuity following treatment in most patients. This study assessed both the response of subfoveal CNV to proton beam irradiation and treatment-related morbidity. We evaluated preliminary results in patients treated with an initial dose of 8 Cobalt Gray Equivalents (CGE) using a relative biological effectiveness (RBE) of 1.1. METHODS AND MATERIALS: Twenty-one patients with subfoveal CNV received proton irradiation to the central macula with a single fraction of 8 CGE; 19 were eligible for evaluation. Treatment-related morbidity was based on Radiation Therapy Oncology Group (RTOG) criteria; response was evaluated by Macular Photocoagulation Study (MPS) guidelines. Fluorescein angiography was performed; visual acuity, contrast sensitivity, and reading speed were measured at study entry and at 3-month intervals after treatment. Follow-up ranged from 6 to 15 months. RESULTS: No measurable treatment-related morbidity was seen during or after treatment. Of 19 patients evaluated at 6 months, fluorescein angiography demonstrated treatment response in 10 (53%); 14 (74%) patients had improved or stable visual acuity. With a mean follow-up of 11.6 months, 11 (58%) patients have demonstrated improved or stable visual acuity. CONCLUSION: A macular dose of 8 CGE yielded no measurable treatment morbidity in patients studied. Fluorescein angiography demonstrated that regressed or stabilized lesions were associated with improved visual acuity as compared with MPS results. In the next phase, a dose of 14 CGE in a single fraction will be used to further define the optimal dose fractionation schedule.

Response of thyroid follicular cells to gamma irradiation compared to proton irradiation. I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival, and cell cycle phase redistribution.

The RBE of protons has been assumed to be equivalent to that of photons. The objective of this study was to determine whether radiation-induced DNA and chromosome damage, apoptosis, cell killing and cell cycling in organized epithelial cells was influenced by radiation quality. Thyroid-stimulating hormone-dependent Fischer rat thyroid cells, established as follicles, were exposed to gamma rays or proton beams delivered acutely over a range of physical doses. Gamma-irradiated cells were able to repair DNA damage relatively rapidly so that by 1 h postirradiation they had approximately 20% fewer exposed 3' ends than their counterparts that had been irradiated with proton beams. The persistence of free ends of DNA in the samples irradiated with the proton beam implies that either more initial breaks or a quantitatively different type of damage had occurred. These results were further supported by an increased frequency of chromosomal damage as measured by the presence of micronuclei. Proton-beam irradiation induced micronuclei at a rate of 2.4% per gray, which at 12 Gy translated to 40% more micronuclei than in comparable gamma-irradiated cultures. The higher rate of micronucleus formation and the presence of larger micronuclei in proton-irradiated cells was further evidence that a qualitatively more severe class of damage had been induced than was induced by gamma rays. Differences in the type of damage produced were detected in the apoptosis assay, wherein a significant lag in the induction of apoptosis occurred after gamma irradiation that did not occur with protons. The more immediate expression of apoptotic cells in the cultures irradiated with the proton beam suggests that the damage inflicted was more severe. Alternatively, the cell cycle checkpoint mechanisms required for recovery from such damage might not have been invoked. Differences based on radiation quality were also evident in the alpha components of cell survival curves (0.05 Gy(-1) for gamma rays, 0.12 Gy(-1) for protons), which suggests that the higher level of survival of gamma-irradiated cells could be attributed to the persistence of nonlethally irradiated thyrocytes and/or the capacity to repair damage more effectively than cells exposed to equal physical doses of protons. The final assessment in this study was radiation-induced cell cycle phase redistribution. Gamma rays and protons produced a similar dose-dependent redistribution toward a predominantly G(2)-phase population. From our cumulative results, it seems likely that a majority of the proton-irradiated cells would not continue to divide. In conclusion, these findings suggest that there are quantitative and qualitative differences in the biological effects of proton beams and gamma rays. These differences could be due to structured energy deposition from the tracks of primary protons and the associated high-LET secondary particles produced in the targets. The results suggest that a simple dose-equivalent approach to dosimetry may be inadequate to compare the biological responses of cells to photons and protons.

Acute effects of whole-body proton irradiation on the immune system of the mouse.

The acute effects of proton whole-body irradiation on the distribution and function of leukocyte populations in the spleen and blood were examined and compared to the effects of photons derived from a (60)Co gamma-ray source. Adult female C57BL/6 mice were exposed to a single dose (3 Gy at 0.4 Gy/min) of protons at spread-out Bragg peak (SOBP), protons at the distal entry (E) region, or gamma rays and killed humanely at six different times thereafter. Specific differences were noted in the results, thereby suggesting that the kinetics of the response may be variable. However, the lack of significant differences in most assays at most times suggests that the RBE for both entry and peak regions of the Bragg curve was essentially 1.0 under the conditions of this study. The greatest immunodepression was observed at 4 days postexposure. Flow cytometry and mitogenic stimulation analyses of the spleen and peripheral blood demonstrated that lymphocyte populations differ in radiosensitivity, with B (CD19(+)) cells being most sensitive, T (CD3(+)) cells being moderately sensitive, and natural killer (NK1.1(+)) cells being most resistant. B lymphocytes showed the most rapid recovery. Comparison of the T-lymphocyte subsets showed that CD4(+) T helper/inducer cells were more radiosensitive than the CD8(+) T cytotoxic/suppressor cells. These findings should have an impact on future studies designed to maximize protection of normal tissue during and after proton-radiation exposure.

Neutron insensitive depolymerization of polyacrylamide for californium-252 photon dosimetry.

A photon dosimeter based on degradation of polyacrylamide (PAA) in dilute aqueous solution has been found to be insensitive to neutrons from Cf-252, independent of photon energy from 34 keVeff to 1.33 MeV, and useful over a dose range of 1 to 100 Gy. Because this dilute polymer solution is virtually 100% water, it is nearly tissue equivalent for photon absorption as well as neutron scatter and attenuation. Radiation response was determined by measuring decreases in viscosity three days after irradiation. The measured response is dose rate independent from 10 to over 300 Gy/h but increases rapidly at lower dose rates. Long-term, radiation-induced viscosity changes were also observed. The many advantages of this tissue equivalent system for photon/neutron dosimetry suggest the need for further studies of the observed over-response at low dose rates.

Determination of the neutron and photon spectra of a clinical fast neutron beam.

A simple technique to determine the neutron and photon spectra of a clinical fast neutron beam is described. This technique involves making narrow beam attenuation measurements with a pair of ionization chambers and an iterative fitting program to analyze the data. A method is also described for determining the first-guess neutron spectrum for input into the iterative program. The results of the analysis yield spectra suitable for use in dose calculation algorithms and dosimetry protocols. Presented here is the first-known published photon spectrum from a clinical machine.

Determination of the air w-value in proton beams using ionization chambers with gas flow capability.

The purpose of this work was to determine the w-value of air for protons using the paired gas method. Several plastic- and magnesium-walled chambers were used with air, synthetic air, nitrogen, and argon flowing gases. Using argon as a reference gas, the w-value of air was measured and ranged from 32.7 to 34.5 J/C for protons with energies encountered in radiotherapy. Using nitrogen as a reference gas, the w-value of air ranged from 35.2 to 35.4 J/C over the same range of proton energies. The w-value was found, at a given energy, to be independent of the ion chamber used. The uncertainty in these measurements was estimated at 5.2% at the 2sigma level. This uncertainty was dominated by the 4.4% uncertainty in the w-value of the reference gas.

Dosimetric evaluation in heterogeneous tissue of anterior electron beam irradiation for treatment of retinoblastoma.

A dosimetric study of anterior electron beam irradiation for treatment of retinoblastoma was performed to evaluate the influence of tissue heterogeneities on the dose distribution within the eye and the accuracy of the dose calculated by a pencil beam algorithm. Film measurements were made in a variety of polystyrene phantoms and in a removable polystyrene eye incorporated into a tissue substitute phantom constructed from a human skull. Measurements in polystyrene phantoms were used to demonstrate the algorithm's ability to predict the effect of a lens block placed in the beam, as well as the eye's irregular surface shape. The eye phantom was used to measure dose distributions within the eye in both the sagittal and transverse planes in order to test the algorithm's ability to predict the dose distribution when bony heterogeneities are present. Results show (1) that previous treatment planning conclusions based on flat, uniform phantoms for central-axis depth dose are adequate; (2) that a three-dimensional heterogeneity correction is required for accurate dose calculations; and (3) that if only a two-dimensional heterogeneity correction is used in calculating the dose, it is more accurate for the sagittal than the transverse plane.

Treatment of macular degeneration with proton beams.

Subfoveal neovascular membranes (SNVMs) are a leading cause of severe visual loss in the elderly in the United States. Previously, the only treatment that could halt progression of this disease was laser photocoagulation, which was, however, accompanied by immediate reduction in visual acuity. A single narrow proton beam was used to irradiate 45 patients to either 8 or 14 Cobalt Gray Equivalent. The alignment technique and dosimetry of these treatments are described. The proton beam direction, range, and modulation were planned with the assistance of an eye-specific planning program. A single anterior beam was used, with patients looking nasally toward a blinking fixation light at an angle of 30 degrees. Patients were aligned using a light field projected through a slit collimator. Patients' positions were monitored during treatment with a short-focal-length camera. Depth dose in a flat phantom was measured with a small-diameter parallel plate ionization chamber. Lateral profiles were measured at several depths with silver halide film. Each treatment session lasted 15 min, of which 1 min consisted of beam delivery. The proton beam stopped in the orbital cavity, delivering no primary proton dose to the brain. Dose to the center of the lens of the involved eye was less than 0.5% of the dose delivered to the macula. Treatments of SNVMs with proton beams require only a short visit to the hospital, little immobilization effort, and a minimal amount of treatment room and beam time. Compared to previous treatment trials using x-ray beams, the dose to nonocular tissues is reduced significantly.

Range, range modulation, and field radius requirements for proton therapy of prostate cancer.

The Loma Linda University Proton Treatment Facility has treated over 5,000 patients for prostate cancer. Other institutions may find information regarding field size and range requirements for this population of patients useful for designing new proton beamlines. The maximum range, range modulation, and maximum field radius for 240 fields of prostate patients undergoing treatment were sampled and analyzed. Most fields required a range less than 290 mm of water, a modulation width less than or equal to 120 mm, and a radius less than 75 mm.

Combination of pGL1-TNF-alpha gene and radiation (proton and gamma-ray) therapy against brain tumor.

The major goal of this study was to determine if treatment with the newly constructed plasmid vector for tumor necrosis factor-alpha (pGL1-TNF-alpha) could enhance the radiation-induced growth reduction of C6 rat glioma. In addition, two different forms of ionizing radiation (gamma-rays and protons) were utilized. Body and spleen mass, leukocyte blastogenesis, and flow cytometry analysis of cell populations in blood and spleen were performed to detect toxicity, if any, and to identify mechanisms that may correlate with the anti-tumor action of combination therapy. C6 tumor cells were implanted subcutaneously into athymic mice and allowed to become established before treatment initiation. pGL1-TNF-alpha was injected into the implanted tumors, which were then irradiated 16-18 hr later; each modality was administered three times over 8-9 days. The addition of pGL1-TNF-alpha significantly enhanced the anti-tumor effect of radiation (p < 0.05). The effect was more than additive, since pGL1-TNF-alpha alone did not slow tumor progression and radiation alone had only a modest effect. Administration of pGL1-TNF-alpha together with proton radiation resulted in tumor volumes that were 23% smaller than those following pGL1-TNF-alpha + gamma-ray treatment; a similar differential in tumor size was observed in the groups receiving only radiation. Body weights and blood and spleen cell analyses did not reveal treatment-related toxicity. High basal proliferation of blood leukocytes and increased B cell levels in the spleen were associated with pGL1-TNF-alpha + 60Co (gamma-radiation) or proton treatment. Overall, the results suggest that the pGL1-TNF-alpha/radiation combination is effective and safe under the conditions employed. This is the first study to combine gene and proton radiation therapy and to show, under controlled experimental conditions, that proton radiation may have a greater effect against malignant tumors compared to the same physical dose of gamma-radiation.

Deduction of the air w value in a therapeutic proton beam.

Utilization of air-filled ionization chambers with 60Co-based reference calibrations in proton dosimetry requires application of water to air stopping power ratios and the mean energy required to produce an ion pair (W or w). Accepted uncertainties in current w values for protons leads to a dosimetric uncertainty of 4 per cent when ionization chambers are employed to measure absorbed dose. For this reason, proton dosimetry protocols recommend the use of calorimetry as the absorbed dose standard. We used calorimetry in conjunction with an ionization chamber with 60Co reference calibrations to deduce the proton w value in the entrance region of a 250 MeV proton beam: 34.2 +/- 0.5 eV. Application of this w value, with its 1.5 per cent uncertainty, allows determination of dose in therapeutic proton beams, with uncertainties comparable to photon and electron values.