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Effect of variation in the energy spectrum of a cyclotron-produced fast neutron beam in a phantom relevant to its application in radiotherapy.

The fast neutron spectrum of the beam produced by the MRC cyclotron at the Hammersmith Hospital has been measured in air and at several depths in a water phantom using three field sizes. The neutron spectra were determined both by a set of six threshold detectors and by a liquid scintillator spectrometer. Where a direct comparison of the two methods was possible the agreement was satisfactory. It was found that the shape of the spectrum, above 3 MeV, is unchanged with depth in the phantom, but for each field size the neutron fluence between 0.5 and 3.5 MeV increases significantly and reaches a maximum and the mean energy a minimum. This minimum decreases with increase in field size. Values of the kerma ratio in ICRU muscle to both that in A--150 plastic and bone were calculated and found to vary by less than 0.5% with depth in the phantom: that of carbon to ICRU muscle varied by 5%, and values of W for methane-based tissue-equivalent gas were found to change by less than 1%. Variations in biological response with changes in neutron spectrum are also discussed, together with the clinical significance of the results.

Fast Neutrons↗

[Dermatofibrosarcoma protuberans. Results of radiosurgical therapy by photon and electron rays or fast neutrons].

The dermatofibrosarcoma protuberans, a rare entity of soft tissue sarcomas, is specified as a tumor of intermediate malignancy because of its marked tendency to form local recurrences. Regarding the prevention of local recurrences, the results of combined radiosurgical therapy (n = 13) could be improved in our patients by the application of fast neutrons (n = 6). Despite multiple previous operations for recurrences, a reliable prevention of local recurrences (average follow-up period 5.5 years) was achieved in all patients by neutron irradiation with focal doses of approximately 9 Gy. One patient with multiple macroscopic recurrences received two neutron series with 17 Gy. At seven years, she is still recurrence-free. We consider the postoperative irradiation of the dermatofibrosarcoma protuberans with fast neutrons following to primary tumor excision as method of choice for a reliable prophylaxis of local recurrences, because this method allows to dispense with major radical surgery.

Adult↗

In vivo elemental partition analysis using fast neutrons. A tool for testing the efficacy of new clinical interventions.

The nutritional status of patients can be evaluated by monitoring changes in body composition, including depletion of protein and muscle; distribution of adipose tissue; and changes in hydration status, and bone or cell mass. Fast neutron activation (for N and P) and neutron inelastic scattering (for C and O) are used to assess in vivo elements characteristic of specific body compartments. Nonbone phosphorus for muscle is measured by the 31P(n,alpha)28Al reaction, and nitrogen for protein via the (n,2n) fast neutron reaction. The carbon-to-oxygen (C/O) ratio is used to measure distribution of fat and lean tissue in the body and to monitor small changes in lean mass and its quality. In addition to evaluating the efficacy of new treatments, the method is used to study the mechanisms of depletion of lean tissue with aging.

Adipose Tissue↗

Microdosimetry of irregular field paraffin collimation in fast neutron therapy.

The King Faisal Specialist Hospital and Research Centre is the only fast neutron therapy facility to utilize paraffin collimation for irregular beam ports. The application of this treatment modification to clinical practice required the microdosimetric characteristics of paraffin to be established. Measurements were made with a tissue equivalent (Rossi) proportional counter at different spatial locations in a water phantom and in air. The neutron beam was shaped by a 10 x 10 cm paraffin collimator. The analytically derived effective relative biological effectiveness (RBE) for 80% survival was approximately 3.5, which is similar to the standard 10 x 10 cm Benelex collimator and is in good agreement with empirical biological observations for this neutron beam.

Calibration↗

[Primary lung cancer treated with fast neutron].

Forty-nine patients with primary lung cancer were treated with fast neutron (average energy, 6 MeV) by so-called mixed therapy method at the Institute of Medical Science, University of Tokyo. Control group (Linacx-ray, 10 MV) was not randomized one, however, these patients were treated by the same chief radiotherapist (Dr. Iino) at Shizuoka Prefectural Hospital and its interval was almost the same to neutron group. The crude survival rate did not show any significant difference between them except for 1 year survival of Stage II (p less than 0.05). Radiation pneumonitis and tumor regression were thought to be almost the same. The incidence of pneumothorax (3/49) was somewhat higher than the x-ray group (3/119) but there was no significant difference. We are now planning a new mixed therapy method which has short time interval (less than 3 hours) between neutron and x-ray irradiation in expectation of decrease of shoulder in x-ray surviving fraction curve.

Fast Neutrons↗

Fast neutron therapy for malignant astrocytomas. A review.

The treatment of supratentorial malignant gliomas has continued to be a major problem for neurosurgeons and oncologists. Post-operative conventional radiotherapy is known to prolong survival and to enhance the quality of life. Local persistence of tumor kills the majority of patients. Fast neutron irradiation is being utilized to treat malignant gliomas based on its reputed radiobiological advantages for treatment of large tumors and the encouraging preliminary reports showing tumor eradication in post-radiation biopsy and autopsy specimens. This paper reviews the results of fast neutron irradiation alone and in combination with photons and hypoxic cell sensitizers. Survival comparisons do not show any superiority for neutrons compared to conventional radiation. However, post-neutron radiation tissue samples have shown less aggressive and minimal residual tumor in many instances. At the same time radiation necrosis has emerged as a significant problem. In summary, even though neutron irradiation can eradicate malignant gliomas a therapeutic window has yet to be identified.

Astrocytoma↗

[Fast neutrons in the treatment of soft tissue sarcomas].

Results of treatment of 101 cases of soft tissue sarcoma are presented in the paper. Preoperative irradiation technique and radical program of treatment are described. Combined radiation and surgical treatment was given to 45 patients whereas conservative--to 56. Sixty-three cases received adjuvant combination chemotherapy. Response and three-year survival rates were compared to those in control group treated by photons. The results observed in patients of combined and conservative treatment groups who had been irradiated with fast neutrons proved significantly better than in controls. These data suggest vistas in application of fast neutron irradiation for the treatment of soft tissue sarcomas.

Adolescent↗

A method for selective evaluation of the effectiveness of fast neutrons in radiotherapy.

A methology is proposed for extracting and analyzing specific fast neutron effects on radiotherapy. This should be applied to the 1,500 patients treated at NIRS, Chiba in the past ten years. As the patients have been treated with different modalities based on generally combined radiation or neutron boost techniques at first the biologically equivalent doses per fraction for the photon and neutron component according to the Ellis concept were derived. In a second step treatment parameters, as the dose components and total dose as well as diagnostic parameters (tumor typing, grading and staging) will be related to the clinical outcome (survival, local control etc.). This may be done by multivariate discriminant or survival analysis.

Analysis of Variance↗

A variety of fast neutron beams for radiobiological research.

The design and construction of a new fast neutron facility and first dosimetric results obtained from seven neutron beams are presented. The neutrons are produced by bombarding beryllium targets with protons and deuterons from our K = 32 negative ion cyclotron. The dose rate in air 1 m distance from the thick target within a 13 x 13 cm2 field amounts to about 50 cGy/min at 30 microA of 32 MeV protons.

Beryllium↗

The multileaf collimator for fast neutron therapy at Louvain-la-Neuve.

The multileaf collimator of the fast neutron therapy facility at Louvain-la-Neuve is described, as well as some of the physics experiments performed in order to evaluate the attenuation of neutron beams in different materials and thus optimize the composition of the collimator leaves. The multileaf collimator consists of two sets of 22 leaves each, which can be moved independently. They are made of iron and their thickness is 95 cm. Seven borated polyethylene disks are located in the distal part of the leaves in order to absorb more efficiently the low-energy component of the neutron spectrum. The width of the leaves is 1 cm at their distal part. The leaves can move 11 cm outwards and 6 cm inwards from their reference position, and field sizes up to 25.7 x 24.8 cm, as well as irregular field shapes, can be obtained. The inner part of the leaves and their two sides are always focused on the target. The complete multileaf collimator can rotate around the beam axis, from -90 degrees to +90 degrees from the reference position. The width of the penumbra (80-20% isodoses) is 0.64 cm and 1.17 cm at the depth of the maximum buildup and at 10 cm in depth respectively, for a 10 x 10 cm field size. The collimator is adequate for the energy of the p(65)+Be neutron beam of Louvain-la-Neuve and has been adapted to the fixed vertical beam. It has been designed following the original plans of Scanditronix, adjusted and fully assembled at the workshop of the Centre de Recherches du Cyclotron (CRC). Systematic measurements were performed in order to optimize the design and the composition of the leaves. In particular the attenuations of the actual beam and of monoenergetic neutron beams were measured in different materials such as iron and polyethylene. Above (upstream) the multileaf collimator, a fixed pre-collimator (iron thickness 50 cm; section 1 x 1 m) defines a conical aperture aligned on the largest opening of the leaves. It contains the two transmission chambers and a 2 cm thick polyethylene layer used for hardening the beam.

Belgium↗

Treatment results of fast neutron irradiation in soft tissue sarcomas.

PURPOSE: Surgery is the standard treatment of soft-tissue sarcomas. Adjuvant radiotherapy with photons after less radical resection can improve local control. The rate of tumor control achieved in patients with G1 and G2 soft tissue sarcomas incompletely resected and treated postoperatively with neutron irradiation is similar to that seen in patients undergoing complete tumor resection and adjuvant photon irradiation. PATIENTS AND METHODS: At the Department of Radiotherapy and Radiation Oncology of the University of Münster, 61 patients with soft tissue sarcomas were irradiated postoperatively with fast neutrons. Mainly tumors of low or intermediate malignancy (R0; 27%; R1, 21%; R2, 52%) were treated. Malignant fibrous histiocytoma, liposarcoma, and neurogenic sarcomas dominated. 46 patients were irradiated with fast neutrons alone, and 15 patients were treated with mixed beam therapy (photons and neutrons). RESULTS: The median follow-up period was 44 months. Overall five-year survival probability analysed by Kaplan-Meyer method was 42.5%. The local control rate was 57.7%. 15 patients showed complete remission, 18 patients had a partial remission. Only 11% of the patients showed grade III and IV side effects during neutron irradiation. CONCLUSION: Neutron irradiation is efficocious in treating highly and intermediately differentiated soft tissue sarcomas. The result of surgical resection seems to be a very important prognostic factor for patients with soft tissue sarcomas.

Adult↗

Preliminary clinical results from U.S. fast neutron teletherapy studies.

Over 700 patients with cancer have been treated with fast neutron beams since 1972 in three U.S. programs at the M.D. Anderson-TAMVEC (Houston and College Station, Texas), University of Washington (Seattle, Washington), and MANTA (Naval Research Laboratory, Washington, D.C.). Clinical applications are about to start at the Fermilab (Batavia, Illinois) and Cleveland Clinic-NASA (Cleveland, Ohio). To date, studies have included: 1) effects of different treatment patterns and doses; 2) responses of several tumor types at many anatomic sites; and 3) acute and long-term normal tissue tolerances. Responses of several cancers, such as extensive epidermoid carcinoma of the cervix and "fixed" metastatic cervical adenopathy, have been encouraging. In patients with glioblastoma multiforme, good tumor responses have not lengthened survival compared with the following conventional radiation therapy. Both local tumor control and "cure" have been compromised by the inclusion of patients with very extensive cancers. In general, treatment has been well tolerated. These preliminary studies provide the basis for planned clinical trials.

Carcinoma, Squamous Cell↗

Metal ions protect DNA against strand breakage induced by fast neutrons.

Single and double strand breaks (SSB and DSB) are induced by fast neutrons in plasmid (pBR322) DNA in 1 mM potassium phosphate buffer (pH 7.25). Increasing the concentration of monovalent (Na+, Cs+, Li+), divalent (Mg2+, Ca2+) and trivalent (Al3+, Co3+ (NH3)6) metal cations strongly decreases the yield of DSB. The extent of the observed protection depends on the valence of the cation. The production of SSB is only slightly decreased, except for Al3+ and Co3+ (NH3)6, whose effects are particularly large (complete protection at 1 and 0.1 mM respectively). Circular dichroism spectra show that Al3+ induces an important structural change of DNA at the ion concentration where the protection becomes total. This change is probably a condensation (collapse), as in the well-known case of Co3+ (NH3)6. Our results suggest two mechanisms of protection by metal ions: (i) the induction of structural changes of DNA, that render less accessible the critical sites of attack by OH. radicals; and (ii) the stabilization of the double helical regions between two close-set nicks on opposite strands, that hinders the effective double strand breakage of DNA.

Cations↗

A comparison of thermal enhancement ratios for fast neutron and x irradiation of two normal tissues in rodents.

The effects of a hyperthermal treatment of one hour on radiation damage to baby rat cartilage and mouse intestine were compared for 250 kVp X irradiation and cyclotron-produced neutron irradiation (mean energy of about 7.5 MeV). Heat, in the range 41.0 degrees C-43.0 degrees C, caused no observable gross tissue injury when given alone. When heat was given immediately before radiation, the radiation damage was enhanced. There was no qualitative differences between response after fast neutrons and after X rays. Thermal enhancement ratios (TER) were similar for the two tissues and were not affected by the type of radiation used. Thus, the relative biological effectiveness (RBE) of fast neutrons compared with X rays was not markedly altered by combining radiation with hyperthermia.

Animals↗

DNA radiolysis by fast neutrons. II. Oxygen, thiols and ionic strength effects.

Plasmid DNA was irradiated with fast neutrons, and the protection by cysteamine against strand breakage (ssb and dsb) was evaluated in the presence and absence of oxygen. In the absence of cysteamine no radiosensitizing effect of oxygen was observed. In anoxia the protection factors, PF(ssb) and PF(dsb) of 1 mM cysteamine (in 50 mM potassium phosphate solution) were lower than the PFs observed with gamma-irradiation. The results agree with the radical repair model, in which the thiol competes with the oxygen produced inside the anoxic neutron-irradiated system, according to the 'oxygen-in-the-track' hypothesis. At low ionic strength in air-saturated solutions, positively charged cysteamine protects more efficiently than negatively charged thiolactate. The dependence of the PFs on the charge of the thiol can be explained by the condensation of counter-ions and depletion of co-ions around DNA, predicted by Manning's theory. Based on the same theory, we propose here an explanation of the ionic strength or by thiolactate at low ionic strength is largely due to scavenging of OH. radicals in the bulk solution. At low ionic strength the PF(ssb) of cysteamine is higher for neutrons than for gamma-irradiation. This might suggest different primary lesions for the two types of irradiation.

Cysteamine↗

Cyclotron fast neutron RBE for various normal tissues.

The relative biological effectiveness (RBE) values of fast neutrons as a function of dose in the range of dose per fraction being used clinically are reported for effects on several normal mouse tissues. The specific tissues examined were: thymus, spleen, white blood cells (WBC), testes, and small intestine. The RBE values for damage to the thymus (1.2), spleen (1.2), WBC (1.0), and testes (3.0) were independent of neutron dose size. In contrast, the RBE for the small intestine varied between 2.7 and 3.4 and was dependent on the size of the neutron dose. The RBE for intestinal death (2.4) and hematopoietic death (1.1) also is reported.

Animals↗

Use of fast neutrons for measuring muscle.

Elemental Partition Analysis (EPA) is a new approach to body composition. A major element of the body is measured and then, by means of other measurements, is partitioned to the contributing body compartments. We developed a model for measuring total body muscle by applying the EPA method to total body phosphorus (TBP). We measure TBP (head excluded) by in vivo fast neutron activation analysis using the reaction 31P(n, alpha)28 Al. The main contributors to TBP are the bone and skeletal muscle. Adipose tissue and the liver contribute less than 3%. We use dual-energy X-ray absorptiometry (DXA) to evaluate the contribution of bone to TBP. Corrections are applied for the small contributions of the liver and adiopose tissue to TBP to derive muscle phosphorous. The technique requires high precision measurements for both TBP (+/- 2%) and DXA (+/- 1%). The total body radiation exposure for measuring human subjects is 0.60 mSv. We observed that nitrogen can also be measured by fast neutron activation analysis through the (n,2n) reaction, simultaneously with TBP.

Adipose Tissue↗

Fast neutrons in the treatment of locally advanced breast cancer.

The clinical investigation of fast neutrons at Hammersmith Hospital included 17 patients who between them had 20 T4 breast cancers. The majority of these tumours were ulcerated and all were painful. Ten had recurred after multiple other therapies. Complete local regression was achieved in all but one (95%) and no tumour recurred. Symptoms were relieved in all cases. Median survival was 26 months. Three patients developed small areas of skin necrosis following trauma of previous radiation. All the neutron treated breasts became fibrosed, but this was painless. Neutron treatment needed only 12 attendances over 28 days, in contrast to the best results from photon therapy which required 6-7 weeks followed by implant of radioactive wire and/or surgical excision. One patient who had bilateral tumours received neutrons to the left breast and X-ray therapy (photons) to the right. The photon treated tumour did not completely regress and recurred. The neutron treated one completely regressed and did not recur. Neutrons were also more effective than tamoxifen which causes complete regression in only about 30% of cases. It is suggested that neutron therapy is indicated for locally advanced tumours which do not respond to hormones. Since metastases were a common cause of death, there remains a need for an effective adjuvant treatment, acceptable to elderly patients.

Adult↗