Heavy Charged Particle Beams Research Articles

DNA double-strand breaks in mammalian cells exposed to gamma-rays and very heavy ions. Fragment-size distributions determined by pulsed-field gel electrophoresis.

The spatial distribution of DNA double-strand breaks (DSB) was assessed after treatment of mammalian cells (V79) with densely ionizing radiation. Cells were exposed to beams of heavy charged particles (calcium ions: 6.9 MeV/u, 2.1.10(3) keV/microm; uranium ions: 9.0 MeV/u, 1.4.10(4) keV/microm) at the linear accelerator UNILAC of GSI, Darmstadt. DNA was isolated in agarose plugs and subjected to pulsed-field gel electrophoresis under conditions that separated DNA fragments of size 50 kbp to 5 Mbp. The measured fragment distributions were compared to those obtained after gamma-irradiation and were analyzed by means of a convolution and a deconvolution technique. In contrast to the finding for gamma-radiation, the distributions produced by heavy ions do not correspond to the random breakage model. Their marked overdispersion and the observed excess of short fragments reflect spatial clustering of DSB that extends over large regions of the DNA, up to several mega base pairs (Mbp). At fluences of 0.75 and 1.5/microm2, calcium ions produce nearly the same shape of fragment spectrum, merely with a difference in the amount of DNA entering the gel; this suggests that the DNA is fragmented by individual calcium ions. At a fluence of 0.8/microm2 uranium ions produce a profile that is shifted to smaller fragment sizes in comparison to the profile obtained at a fluence of 0.4/microm2; this suggests cumulative action of two separate ions in the formation of fragments. These observations are not consistent with the expectation that the uranium ions, with their much larger LET, should be more likely to produce single particle action than the calcium ions. However, a consideration of the greater lateral extension of the tracks of the faster uranium ions explains the observed differences; it suggests that the DNA is closely coiled so that even DNA locations several Mbp apart are usually not separated by less than 0. 1 or 0.2 microm.

Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma

Purpose: To review the results and evaluate the prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. Methods and Materials: We reviewed the records of 74 patients with locally recurrent nasopharyngeal carcinoma treated at the University of California, San Francisco between 1957 and 1995. The histologic types included squamous cell carcinoma in 6 (8.1%), nonkeratinizing carcinoma in 48 (64.9%), and undifferentiated carcinoma in 20 (27%) cases. The site of recurrence was in the primary in 46 (62.2%), in the neck nodes in 20 (27%), and in both sites in 8 (10.8%) patients. The recurrent disease was Stage I in 10 (13.5%), Stage II in 16 (21.6%), Stage III in 20 (27%), and Stage IV in 28 (37.9%) patients. Thirty-seven (50%) patients developed recurrence within 2 years and 58 (78.4%) within 5 years after initial treatment. Radiotherapeutic techniques used in the retreatment of primary recurrence consisted of external beam radiotherapy (EBRT), intracavitary brachytherapy, heavy-charged particle beam, and gamma knife, alone or in combination. Reirradiation doses ranged from 18 to 108 Gy, with a median dose of 60 Gy. Treatment of recurrent neck nodes consisted of radical neck dissection (RND) ± intraoperative radiotherapy (IORT), or EBRT ± hyperthermia, or chemotherapy ± hyperthermia. Chemotherapy was used in 22 (30%) patients. Median follow-up was 20 months (range: 2 to 308 months). Results: The 3-, 5-, and 10-year actuarial overall survival following retreatment were 49, 37, 18%, respectively. Thirty-six patients (49%) were free of further local-regional recurrence after retreatment. The 3-, 5-, and 10-year local-regional progression-free rates were 52, 40, and 38%, respectively. On univariate analysis, histologic type ( p < 0.0001), interval to recurrence ( p = 0.034), and treatment modality for early-stage disease ( p = 0.01) were significant prognostic factors for overall survival, with age being marginally significant ( p = 0.053). For local-regional progression-free rate, only histology was significant ( p = 0.035). On multivariate analysis, age ( p = 0.026), histology ( p = 0.015), and interval to recurrence ( p = 0.030) were significant for overall survival, and only histology ( p = 0.002) and presence of complications ( p = 0.016) were significant for local-regional progression-free rate. Of the 64 reirradiated patients, late complications were documented in 29 (45%) patients. The late complications were permanent in 21 (33%) and severe in 15 (23%) patients. Conclusion: Retreatment using radiotherapy alone or in combination with other treatment modalities can achieve long-term local-regional control and survival in a substantial proportion of patients with locally recurrent nasopharyngeal carcinoma. Age, histology, and interval to recurrence were independent prognostic factors for overall survival, but only histology and presence of complications were significant for local-regional progression-free rate.

112 Prognostic factors in the re-treatment of locally recurrent nasopharyngeal carcinoma

Materials & Methods: We reviewed the records of 74 patients with locally recurrent nasophatyngeal carcinoma treated at the University of California, San Francisco between 1957 and 1995. The histologic types included squamous cell carcinoma in 6 (8.1%), non-keratinizing carcinoma in 48 (64.9%), and undifferentiated carcinoma in 20 (27%) cases The site of recurrence was in the primary in 46 (62.2%), in the neck nodes in 20 (27%) , and in both sites in 8 (10.8%) patients. The recurrent disease was stage I in 10 (13.5%), stage II in 16 (21.6%), stage Ill in 20 (27%), and stage IV in 28 (37.9%). Thirty-seven (50%) patients developed recurrence within 2 years and 58 (78.4%) within 5 years after initial treatment. Radiotherapeutic techniques used in the re-treatment of primary recurrence consisted of external beam radiotherapy (EERT), intracavitary brachytherapy, heavy charged particle beam, gamma knife alone or in combination. Re-irradiation doses ranged from 18 to 108 Gy with a median dose of 60 Gy. Treatment of recurrent neck nodes consisted of radical neck dissection (RND) + intraoperative radiotherapy (IORT), or EBRT + hyperthermia, or chemotherapy + hyperthermia. Chemotherapy was used in 22 (30%) patients. Median follow-up was 20 months (range: 2 to 308 months).

Absorbed Dose Measurement and LET Determination with TLDs in Space

For determination of the average LET in complex mixed radiation fields, a new method was developed using the LET dependent changes of the peak height ratios in thermoluminescence glow curves (HTR). Various types of standard and laboratory made TLDs were calibrated in alpha, beta, gamma and neutron fields and in heavy charged particle beams. These calibrated TL phosphors were used on space station MIR in order to determine the equivalent dose. During the long-term mission of 5 months in the summer of 1991 the dose rate was 0.24 ± 0.01 mGy.d -1 with an average LET (tissue) of 6.2 ± 0.25 keV.μm -1 , and during an 8 day short-term mission in October 1991 0.204 ± 0.003 mGy.d -1 with a LET of 6.5 ± 0.30keV.μm -1 . The new method was also used for measurements carried out on satellite PHOTON-8 (1992) and on satellite BION-10 (1993) to obtain more information about the changes of the average LET of space radiation with the variation of the shielding. An increase in the average LET from 0.35 to 10keV.μL -1 dependent on the absorber thickness from 1,14mg.cm -2 to 2.5 g.cm -2 was measured. The method was also used for determination of the characteristics of the low energy electron component of space radiation on BION-10 and for the determination of the average LET on board high altitude aircraft.

Calculated Bragg curves for ionization chambers of different shapes

Bragg curves for proton beams are different in shape if measured with different detectors, such as silicon diodes, extrapolation, and thimble chambers. Calculations with an analytic algorithm are presented which show that such differences are caused, at least in part, by the shapes of the detectors. Similar differences must be expected for all beams of heavy charged particles. Dose conversion factors representing the conversion of a measured dose into dose in water are discussed.

New Trends in Scintillation Detection for Dose and Radiation Quality Monitoring Purposes

Two scintillation detectors were constructed which are useful in the analysis of prompt and delayed components of light from organic scintillators. A design based on a direct 100 MHz digitisation of signals was used to analyse light from some 'slow' scintillators like naphalene (pure and in toluene) and anthracence. According to the model of the mechanism of scintillation of Voltz and Lopes de Silva the ratio of intensities of prompt (fast) and delayed (slow) components depends upon dE/dx of the heavy charged particle beam. A faster device, equivalent to a 1 GHz digitiser, based on the principle of a single photon counter (SPC) was also constructed and used to analyse the shapes of scintillation pulses from 'fast' scintillators, with a particular reference to NE102A. The paper deals with the construction of the devices, their functioning and cites preliminary results obtained with them.

Instrumentation for treatment of cancer using proton and light-ion beams

Clinical trials using accelerated heavy charged-particle beams for treating cancer and other diseases have been performed for nearly four decades. Recently there have been worldwide efforts to construct hospital-based medically dedicated proton or light-ion accelerator facilities. To make such accelerated heavy charged-particle beams clinically useful, specialized instruments must be developed to modify the physical characteristics of the particle beams in order to optimize their biological and clinical effects. This article reviews the beam modifying devices and associated dosimetric equipment developed specifically for controlling and monitoring the clinical beams.

Acoustic effect of pulsed high-energy proton beams

Experimental data on the generation of acoustic radiation in solid targets by pulsed high-energy proton beams are outlined. The features of ultrasound generation in solids by beams of heavy charged particles are analyzed, and the possibility of using the acoustic effect of heavy charged particles to investigate the interaction between radiation and condensed media and to determine particle energies is shown.

Dynamic stereotactic radiosurgery in arteriovenous malformation: Preliminary treatment results

From December 1986 through August 1988, 25 patients with intracranial arteriovenous malformations underwent radiosurgery with the dynamic stereotactic irradiation technique. The prescribed dose at isocenter ranged from 50 Gy to 55 Gy, given as a single fraction in 92% of the patients. Field sizes, defined at the 90% isodose surface, varied from 5 mm to 25 mm and were chosen in order to deliver 20 to 25 Gy at the periphery of the malformation. To date, 14 angiographic studies were repeated at 1 year posttreatment. In six patients (43%) a complete obliteration of the lesion was achieved. Late side effects were observed in three patients. Our initial analysis, at 1 year posttreatment, suggests that our results are comparable with those previously reported for other radiosurgical techniques. The linac-based dynamic stereotactic technique appears to be a valid alternative to radiosurgery with the Gamma unit or with heavy-charged particle beams.

Stimulated recombination of atoms accompanying electron cooling of heavy charged particle beams

An analysis is made of the quantum mechanical problem of the stimulated transition of a proton–electron system in the field of a strong electromagnetic wave from the continuum to a bound state having a finite lifetime. Expressions are derived for the intensity of the spontaneous radiation which accompanies the transition of the system from an intermediate bound state to the ground state, and also for the rate of formation of neutral hydrogen atoms. It is found that in the field of an external electromagnetic wave the probability of formation of atoms increases substantially compared with spontaneous recombination.

Distal penetration of proton beams: the effects of air gaps between compensating bolus and patient

These Monte Carlo studies have shown that, if the distal end of range of the proton beam is to be tailored tightly to the target volume, sophisticated treatment planning programs, beam delivery and patient immobilisation techniques have to be developed and details, such as having the compensating bolus fit snugly to the patient's surface, have to be considered. Although the magnitudes of the effects reported here are specific to the components and beam quality in this Harvard Cyclotron Laboratory proton beam line, the principles are general and apply to all heavy charged particle beams. Thus, in the design of a proton beam delivery system, every effort should be made to allow the beam-modifying devices to get very close to the patient or to devise some other means to minimise the separation of patient and bolus.

Neurosurgical applications of ion beams

The program at Donner Pavilion has applied nuclear medicine research to the diagnosis and radiosurgical treatment of life-threatening intracranial vascular disorders that affect more than half a million Americans. Stereotactic heavy-charged-particle Bragg peak radiosurgery, using narrow beams of heavy ions, demonstrates superior biological and physical characteristics in brain over X-and γ-rays, viz., improved dose distribution in the Bragg peak and sharp lateral and distal borders and less scattering of the beam. Examination of CNS tissue response and alteration of cerebral blood-flow dynamics related to heavy-ion Bragg peak radiosurgery is carried out using three-dimensional treatment planning and quantitative imaging utilizing cerebral angiography, computerized tomography (CT), magnetic resonance imaging (MRI), cine-CT, xenon X-ray CT and positron emission tomography (PET). Also under examination are the physical properties of narrow heavy-ion beams for improving methods of dose delivery and dose distribution and for establishing clinical RBE/LET and dose-response relationships for human CNS tissues. Based on the evaluation and treatment with stereotactically directed narrow beams of heavy charged particles of over 300 patients, with cerebral angiography, CT scanning and MRI and PET scanning of selected patients, plus extensive clinical and neuroradiological followup, it appears that Stereotactic charged-particle Bragg peak radiosurgery obliterates intracranial arteriovenous malformations or protects against rebleeding with reduced morbidity and no mortality. Discussion will include the method of evaluation, the clinical research protocol, the Stereotactic neuroradiological preparation, treatment planning, the radiosurgery procedure and the protocol for followup. Emphasis will be placed on the neurological results, including the neuroradiological and clinical response and early and late delayed injury in brain leading to complications (including vasogenic edema, arterial occlusion, venous thrombosis and radiation necrosis). Clinical results in both children and adults will be illustrated and health outcome will be related to the advantages of charged-particle treatment planning, the radiosurgical procedure, dose distribution and dose localization.

The Katz cell-survival model and beams of heavy charged particles

In this paper, we describe how the Katz cell-survival model has been used to predict survival along the central axis of the dose vs depth curve of beams of heavy charged particles. Unmodified beams with sharp Bragg peaks as well as ridge-filter-modulated beams with spread Bragg peaks have been studied. The analysis in terms of this model leads to the definition of twocoefficients, “ion kill” and “gamma kill”, which characterize the radiation quality of the beams. In this way, the relative importance of the primary and secondary (fragmentation) contributions can be assessed easily. Setting the model parameter m equal to 2 yields two interesting results: the survival expression becomes linear-quadratic at low doses and the inactivation cross-section at small values of Z ∗2/β 2 (low-LET) increases as (Z ∗2/κβ 2) 2 in accordance with the Lethal-Potentially Lethal (LPL) model. With this restriction on m and these approximations (low-LET and low dose) and for delayed plating experiments of stationary phase cells (i.e. when repair is complete), the Katz model and the LPL model reduce to the same analytical form (linear-quadratic) with simple expressions linking the constants.

Applications to radiobiology and radiotherapy

The applications of radiobiology to the estimation of risk concern lower doses than the applications to radiotherapy, where the range of dose-per-fraction is 1–10 Gy. The shapes of dose-response curves for various tissues of importance in radiotherapy are therefore much better known than for mutations or carcinogenesis at hazard-level doses. In particular the change of total dose required to achieve a given effect in multifraction radiotherapy is now understood to vary more rapidly with size of dose-per-fraction for late than for early reacting tissues. This is due to a difference in the shapes of the dose-response curves. Knowledge of this difference has already led to better local control of tumors treated with small fractions twice a day, using low-LET photon radiation. Much less change in total dose-per-fraction is necessary for high-LET (neutron or heavy charged particle beams), so that certain types of humor can be selected for high-LET radiotherapy. Comparisons between the effectiveness of neutrons, negative pi-mesons, and beams of charged ions such as helium, carbon, neon or argon depend on the track structure.

Acoustic Pulse Generation in Water by Pulsed Proton Beam Irradiation and its Possible Application to Radiation Therapy

Acoustic pulse generation in water irradiated by pulsed proton beam was observed. The dose rate of the beam was 0.05 Gy/pulse and 0.0025 Gy/pulse. A hydrophone sensitive to the acoustic frequency band between 0 to 300 kHz was used for detection. The detected acoustic pulse in water was qualitatively the same shape as the depth dose distribution of the proton beam, when the depth scale is divided by the sound velocity. The intensity of the generated acoustic pulse is believed to allow monitoring of the radiation dose distribution in patients irradiated by pulsed heavy charged particle beam.

Neutron capture therapy in support of other radiation treatment.

Neutron capture therapy (NCT) appears potentially useful, not only as a treatment modality per se, but also as an adjuvant in the context of established clinical measures to control pathological growth. Since the probability of local control is a steep function of absorbed dose, even a modest specific exposure of neoplasms by such techniques would significantly increase the chances of cure. Such a prospect seems most natural in fast neutron therapy 1,2,3 where slow neutrons are automatically available in the target area. As a promising alternative, it would be possible to combine the use of protons or heavier ions with a booster therapy based on boron compounds and intermediate-energy neutrons.4 Such a situation would be particularly relevant when there are needs both for the precision of heavy charged-particle beams--permitting tailored 3-dimensional dose plans for the treatment of structures visible by computerized imaging methods--and for the particular features of NCT that also aim at eradication of invisible but suspected microsopic growth in larger anatomical regions.

Radioprotection of Mouse Colony Forming Units-Spleen against Heavy-Charged Particle Damage by WR 2721

The effectiveness of S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR 2721) to protect against the heavy-charged particle beams with dose-averaged LET infinity's ranging from 26 to 260 keV/micron was studied using the marrow colony forming units-spleen as a model system. WR 2721 (400 mg/kg) was injected ip 30 min before whole-body irradiation in the plateau ionization region of the Bragg curve. Significant protection was observed at 26, 51, and 135 keV/micron LET values where the data were collected with 20Ne, 28Si, and 40Ar ions, respectively. The largest component of protection was the slope change, where at LET values of 26 and 51 keV/micron the DMFs (slope) were 2.1 and 2.3, respectively, which are very close to the gamma-ray value of 2.4 (gamma LET approximately equal to 0.2 keV/micron). Protection, however, decreased with increase in LET from 51 to 135 keV/micron to the DMF value of 1.2 and no significant protection was observed against 56Fe ions at 260 keV/micron. Significant increases in extrapolation number occurred with gamma rays and neon particles. The results are discussed in terms of charged particle track structure, radiation chemistry, and potential clinical applications.

Degradation of the Bragg peak due to inhomogeneities

The rapid fall-off of dose at the end of range of heavy charged particle beams has the potential in therapeutic applications of sparing critical structures just distal to the target volume. The effects of highly inhomogeneous regions on this desirable depth-dose characteristic are explored. The proton depth-dose distribution behind a lucite-air interface parallel to the beam was bimodal. A second experiment showed little significant effect on the distal depth-dose of protons having passed through a mosaic of teflon and lucite. Anatomic studies demonstrated significant effects of complex fine inhomogeneities on the end of range characteristics. Monoenergetic protons passing through the petrous ridges and mastoid air cells in the base of the skull showed a dramatic degradation of the distal Bragg peak. Heavy ions showed a corresponding degradation in their ends of range. In the worst case in the base of the skull region, a monoenergetic neon beam showed a broadening of the full width at half maximum of the Bragg peak to over 15 mm. A similar effect was found with carbon ions in the abdomen. The authors address the implications of these data for dose computation with heavy charged particles.

Current Considerations in Heavy Charged-Particle Radiotherapy: A Clinical Research Trial of the University of California Lawrence Berkeley Laboratory, Northern California Oncology Group, and Radiation Therapy Oncology Group

Phase I and II radiotherapy trials with accelerated high-energy heavy charged-particle beams have been carried out at the University of California Lawrence Berkeley Laboratory in conjunction with the Northern California Oncology Group and the Radiation Therapy Oncology Group. Clinical experience with several anatomical regions and tumor types has been accumulated. Preliminary observations suggest that toxicity is acceptable with treatment techniques developed for neon ions. Further data must be accumulated for carbon or silicon ion therapy. Initial Phase III trials with neon ions should begin shortly; evaluation of optimal ions and techniques for improved dose localization is ongoing. Future directions for optimization of heavy charged-particle radiotherapy are presented.

A phase I–II trial of heavy charged particle irradiation of malignant glioma of the brain: A Northern California oncology group study

Thirty-nine patients with primary or recurrent glioma of the brain were irradiated wholely or in part with heavy charged particle beams at the University of California Lawrence Berkeley Laboratory in a Phase I–II clinical trial of the Northern California Oncology Group. During the course of this trial, treatment techniques have been developed and tumor doses have been escalated in order to obtain data on normal brain toxicity and response of malignant glioma of the brain. Toxicity has been acceptable with a low level of brain injury. Survival and tumor control has been approximately the same as historical results in glioma of the brain. Further dose escalation is planned together with possible trial of combined modality therapy.