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Fast neutron radiotherapy for soft tissue sarcomas. University of Washington experience and review of the world's literature.

Sixteen patients with inoperable soft tissue sarcomas were treated definitively with fast neutrons at the University of Washington between August, 1970 and May, 1982. Eleven of these 16 patients were treated with curative intent and form the basis of this report. Actuarial plots are shown for local tumor control and survival. This work is placed in the context of worldwide experience in using fast neutrons to treat unresectable soft tissue sarcomas.

Fast Neutrons↗

The effect of bone on dose distributions produced by the Fermi National Laboratory fast-neutron beam.

The dose distortion produced by bone during fast-neutron therapy was studied using a target-to-skin distance of 153 cm, with beams 10 x 10 field size at the surface of a phantom. Doses were measured using several muscle-equivalent ionization chambers in the phantom. Results showed that the dose was reduced by interposing bone-equivalent material between the point in question and the surface of the phantom.

Bone and Bones↗

In vivo measurements of lung corrections for fast-neutron therapy.

Silicon diodes were inserted into the esophagus and bronchus of anesthetized rhesus monkeys in order to measure the corrections to tumor dose resulting from intervening lung tissue during fast-neutron therapy. The derived corrections were applied to tumor doses for patients being treated for cancer of the esophagus on the fast-neutron beam at TAMVEC. In vivo dosimetry performed on these patients using silicon diodes in the esophagus confirmed the accuracy of the lung corrections. The measured dose and calculated dose agreed to within 4% for four different patients. Tha magnitude of the correction is on the order of 16% for the typical esophageal cancer patient. These studies were also done with Cobalt-60 in order to test, against other data, the results obtained with this animal model.

Animals↗

Anal cancer treated by fast neutron radiation.

Ten patients with anal cancer were treated with fast neutrons from the Medical Research Council Cyclotron at the Hammersmith Hospital. In all cases a temporary colostomy was established before treatment commenced. Three of the patients had advanced tumours that were extending into the pelvis; treatment for these patients was palliative and all died within 1 year. Four of the remaining 7 have normal anal function with no evidence of local recurrence of the tumour. Two others developed necrosis in the irradiated area and in another, the tumour recurred locally. The colostomy was re-established in 1 and the 2 others had abdominoperineal resections, after which wound healing was prolonged. A majority of the surviving patients have thus been able to avoid a permanent colostomy.

Adolescent↗

Micronuclei induced by fast neutrons versus 60Co gamma-rays in human peripheral blood lymphocytes.

Here we compared the effectiveness of neutrons ( = 5.5 MeV) versus 60Co gamma-rays in producing micronuclei (MN) in human lymphocytes. To obtain dose-response data, blood samples of six donors were irradiated with doses ranging from 0.1 to 5 Gy for gamma-rays and 0.1-3 Gy for neutrons. A linear dependence of MN yield with dose was found for fast neutrons while for gamma-rays a nonlinear dependence existed. For both radiation qualities no significant interindividual differences were found. Derived relative biological effectiveness values decreased with increasing dose. The MN frequency distributions were overdispersed with respect to the Poisson distribution, with neutrons showing higher dispersion values than with gamma-rays. To compare the repair kinetics of both radiation qualities split-dose experiments were performed. A dose of 4 Gy gamma-rays (3 Gy neutrons) was delivered either as a single exposure or in two equal fractions separated by time intervals ranging from 30 min to 10 h (30 min to 7 h for neutrons). The data showed for gamma-rays a significant decline (30% +/- 10%) in MN yield with interfraction time due to repair of DNA damage. This repair is a continuous process starting almost immediately after the first of the two doses and lasting 3-5 h. For fast neutrons no decline was observed indicating irreparable damage.

Cells, Cultured↗

RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus.

From August, 1977, through January, 1981, the Radiation Therapy Oncology Group sponsored a Phase I study (RTOG 77-09) on the use of fast neutrons for treating inoperable squamous cell carcinomas of the esophagus. A total of 39 evaluable patients were treated with curative intent using either fast neutrons alone or in combination with low LET irradiation as part of a mixed beam fractionation scheme. Actuarial survival curves are presented for both the "neutrons alone" and the "mixed beam" treatment groups. There was no significant survival difference between these groups of patients. The projected survival at two years is less than 10%, which is comparable with megavoltage photon results for an unselected series of patients. The size of the primary lesion and the initial Karnofsky performance status were found to be the most important prognostic indications for prolonged survival. Sixteen of 39 patients were felt to have achieved local clearance of their tumor at some time during their follow-up with the median time until a local recurrence being 17 months. Treatment related complications and patterns of metastatic spread are discussed. In general, it appeared that the response of large tumors to neutron irradiation resulted in necrosis and fistula formation. In many cases this was accompanied by persistent/recurrent tumor within the high dose radiation volume.

Aged↗

Fast neutron treatment as an alternative to radical surgery for malignant tumours of the facial area.

Thirty one patients with very advanced tumours of the maxillary sinus were treated with fast neutrons. Tumour regressed completely in 29 (94%) and subsequently recurred in four (14%). No surgical excision of bone, skin, or nerve was required, and an artificial eye was well tolerated in cases where the eye received the tumour dose and had to be removed. Complications occurred in 10 patients, two of whom had already received radical x ray treatment. The overall duration of neutron treatment was four weeks, and admission to hospital was usually unnecessary. These results compared well with those obtained with surgery. Surgery with curative intent for even moderately advanced tumours of the facial region, particularly the paranasal sinuses, results in deformity, which is often severe and always irreversible. Even so, the cure rate is only about 35%. The high rates of tumour control and the avoidance of severe cosmetic and functional defects after fast neutron treatment make it an alternative to radical surgery in the management of malignant tumours of the facial area.

Eye, Artificial↗

[Results of the treatment with fast neutrons (d.T 13 MeV) in recurrent rectal carcinoma].

PURPOSE: In spite of improved surgical techniques and the use of multiple modality treatment schemes the local recurrence rate of colorectal carcinomas could not be successfully reduced up to now. Besides surgical treatment of local recurrences in some cases radiation therapy may be indicated. PATIENTS AND METHOD: In the Department of Radiotherapy of the University of Münster 37 patients with recurrent rectal carcinoma were treated between the end of 1985 and September 1992 either with fast neutrons alone or with a combined photon-neutron therapy. Eighteen patients received radiotherapy with fast neutrons (14 MeV d,T) alone; the tumor dose was between 10 and 15 Gy neutrons. Nineteen patients were irradiated with a mixed-beam schedule consisting of 30 to 45 Gy photons (X 10 MV) and neutron doses ranging from 5 to 10 Gy. RESULTS: In 30 patients a good or complete pain relief could be observed immediately after the last irradiation. Sixteen out of 37 patients had local tumor regrowth during the follow-up period. The median survival for all 37 patients was 15.9 months. The probability for survival was 86% after 6 months and 61% after 12 months (Kaplan-Meier). The side effects were slight to moderate (EORTC/RTOG I-II). CONCLUSIONS: This therapy showed good results concerning a fast and effective pain relief. Additionally the results seem to show a good effect concerning local control and overall survival in this negatively selected patients.

Adenocarcinoma↗

Fast neutron radiotherapy for locally advanced prostate cancer: results of an RTOG randomized study.

Between June 1977 and April 1983, the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized study investigating fast neutron radiation therapy in the treatment of patients with locally advanced (Stage C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation therapy or fast neutron irradiation used in a mixed-beam treatment schedule (neutron/photon). A total of 91 analyzable patients were entered in the study; 78 of them were treated without major protocol deviations. The two treatment groups were balanced in regard to all major prognostic variables. Actuarial curves for "overall" survival, "determinantal" survival and local/regional control are presented both for the entire group of 91 patients and the 78 patients treated within protocol guidelines. The overall local/regional tumor recurrence rate is 7% for the mixed-beam treated group of patients and is 22% for the photon (X ray) treated group of patients. The difference is statistically significant at the p = 0.05 level. For the entire group of 91 evaluable patients, the 5-year "overall" survival rate is 62% for the mixed-beam-treated group and 35% for the photon-treated group. This difference is also statistically significant (p less than 0.05). However, this statistical significance is lost when the smaller number of patients treated strictly within protocol guidelines is considered. The significance is regained (p less than 0.02) when one looks at "determinantal" survival, which uses active cancer at time of death as the failure endpoint. This study demonstrates that a regional treatment modality, in this case mixed-beam irradiation, can influence both local/regional tumor control and survival in patients with locally-advanced adenocarcinoma of the prostate gland.

Adenocarcinoma↗

Response of a Si-diode-based device to fast neutrons.

Semiconductor devices based on a Si-detector are frequently used for charged particle's detection; one application being in the investigation of cosmic radiation fields. From the spectra of energy deposition events in such devices, the total energy deposited by the radiation in silicon can be derived. This contribution presents the results of studies concerning the response of this type of detector to fast neutrons. First, the spectrum of energy deposition was established in fast neutron radiation fields with average energies from 0.5 to 50 MeV. It was found that these spectra vary significantly with the neutron energy. The comparison with the spectra registered in photon beams permitted an estimation of the part of energy deposited that could be attributed to neutrons. It was found that this part increases rapidly with neutron energy. The possibilities to use this type of detector for neutron detection and dosimetry for radiation protection are analysed and discussed.

Aircraft↗

[IV. Studies on cell biological experiments to the relative biological effectiveness (RBE) of fast neutrons in different phantom depths (author's transl)].

From carcinomas of the collum uteri and from human embryos (10 weeks) primary cell cultures were obtained, irradiated with 60Co-gamma-rays and fast neutrons (6,2 mev), respectively, in doses ranging from 50 to 300 rad in the phantom depth of 3 and 12 cm at 37 degrees C, and the number of mitotically surviving cells was determined. From the survival curves, the values of D37, Do and Dq were determined. The studies have shown that embryonic cells have higher Dq values than the tumor cells under study, while there were no distinct differences in primary radiation sensitivity Do between normal and tumor cells when considering biological variability. The relative biological effectiveness (RBE) of the 6,2 mev neutrons proved clearly dependent on the level of the single dose or of percent survival rate, respectively. The minima of the RBE values were obtained refering to Do (2,2-2,7). From the quotient RBE (tumor cells)/RBE (embryonic cells) ranging from 0.88 to 1.23 depending on the reference system, the different phantom depth and the cell cultures used can be concluded that the stronger biological effectiveness of fast neutrons is not necessarily an additional therapeutical advantage, but that the "anoxic gain factor" and the ensueing increased killing of hypoxic tumor cells has to be considered as the main advantage of neutron therapy. Using the neutron therapy in a phantom depth of 12 cm, a slow increase of the RBE-values can be registered in comparison to the radiation in a depth of 3 cm, if for the formation of the RBE-values the pure dose of neutrons without reference to the gamma-ray part will be employed. When we use for the formation of the RBE-values the neutron-dose including the dose for the corresponding gamma-ray part, a change of the RBE on the phantom depth tested here is not detectable.

Culture Techniques↗

Dose estimations of fast neutrons from a nuclear reactor by micronuclear yields in onion seedlings.

Irradiations of onion seedlings with fission neutrons from bare, Pb-moderated, and Fe-moderated 252Cf sources induced micronuclei in the root-tip cells at similar rates. The rate per cGy averaged for the three sources, , was 19 times higher than rate induced by 60Co gamma-rays. When neutron doses, Dn, were estimated from frequencies of micronuclei induced in onion seedlings after exposure to neutron-gamma mixed radiation from a 1 W nuclear reactor, using the reciprocal of as conversion factor, resulting Dn values agreed within 10% with doses measured with paired ionizing chambers. This excellent agreement was achieved by the high sensitivity of the onion system to fast neutrons relative to gamma-rays and the high contribution of fast neutrons to the total dose of mixed radiation in the reactor's field.

Fast Neutrons↗

Fast neutron radiotherapy for locally advanced prostate cancer. Final report of Radiation Therapy Oncology Group randomized clinical trial.

Between June 1977 and April 1983 the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized trial investigating the use of fast neutron radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation or fast neutron radiation used in a mixed-beam (neutron/photon) treatment schedule. A total of 91 analyzable patients were entered into the study, and the two patient groups were balanced with respect to the major prognostic variables. Actuarial curves are presented for local/regional control and "overall" survival. Ten-year results for clinically assessed local control are 70% for the mixed-beam group versus 58% for the photon group (p = 0.03) and for survival are 46% for the mixed-beam group versus 29% for the photon group (p = 0.04). This study suggests that a regional method of treatment can influence both local tumor control and survival in patients with locally advanced adenocarcinoma of the prostate gland.

Adenocarcinoma↗

Repair of potentially lethal damage in yeast induced by fast neutrons.

Survival curves of 3 diploid (D7) yeast strains: one wild-type, one deficient in excision of pyrimidine dimers (UV-sensitive) and one blocked in DNA double-strand-break repair (X-ray-sensitive), were compared after irradiation with cyclotron-produced fast neutrons. It was observed that both the UV-sensitive (rad3/rad3) and the X-ray-sensitive (rad52/rad52) mutants were more sensitive to neutrons than the wild-type. The role of DNA double-strand-breaks in neutron-induced cell death was further studied by comparing the relative sensitivity of the rad52/rad52 mutant to gamma-rays and fast neutrons. A comparison of the dose modification factors revealed that the deficiency in DNA double-strand-break repair did not make the yeast cells more sensitive to neutrons than to photons, which suggests that lesions of a different type may also be produced by neutrons. Survival curves obtained upon immediate plating and after delayed plating of neutron-irradiated cells showed that all 3 yeast strains were efficient in liquid holding recovery. The role of different repair pathways in cellular recovery from neutron-induced lethal damage is discussed.

DNA Repair↗

The RBE of fast neutrons for in vitro inactivation of human tumour cells determined by the ratio of mean inactivation doses.

In an effort to clarify the relationship between sensitivity of human tumour cells to low-LET and to fast neutron irradiation, 10 human tumour cell lines were exposed to cobalt gamma-rays and to 60 MeV (p -> Be+) neutron beam. The data were pooled with results of 31 human tumour cell lines previously published. The analysis of date using the linear-quadratic model indicated that not only alpha values increased after neutron irradiation, but so did beta values too, although to a lesser extent. The mean inactivation dose (MID) was derived for each cell line from the linear-quadratic parameters after low-LET and high-LET exposure. MID values following neutron irradiation were closely correlated to those after gamma-ray irradiation. In these 41 cell lines, the extreme values of RBE derived by the ratio of MID varied by a factor of 3 among the cell lines. RBE was positively correlated to photon MID, meaning that intrinsically radiation resistant tumour cells have a higher neutron RBE, on average. Similar findings were observed if alpha ratios were used instead of MID ratios. In addition, the RBE/dose variations were more marked in cells with the higher RBE. Taken together, these data suggest that, although considerable variations exist among human tumour cell lines, intrinsically radioresistant cells are relatively more sensitized when exposed to high LET beams than radioresponsive tumours. An 'intrinsic gain factor' may thus be expected in irradiating radiation resistant tumours with fast neutrons, in addition to the hypoxic or kinetic gain factors. Because the quadratic component is still present after neutron irradiation, we suggest using MID ratio as a reference RBE when comparing survival curves of cells exposed to radiations of different qualities.

Cell Survival↗

Radionuclide production and partial radiochemical characterization following fast neutron irradiation of mouse spleens.

When radiotherapy patients are irradiated with fast neutron beams (energies greater than 20 MeV), positron emitting radionuclides (15O, 13N, 11C) are created in their tissues. Capillary blood flow can be determined in the irradiated tissue by measuring the washout of the 15O. The chemical form of these positron emitting nuclides is important when assumptions about their transport in the development of a blood flow model are being made. In the present work, normal mouse spleen tissue was used as a model system for these studies. The mouse spleen was activated by whole mouse irradiation using the M.D. Anderson Hospital neutron beam produced by 42 MeV protons impinging on a beryllium target. Results of cellular studies and large molecule precipitation measurements (1) show that at least 65% of 15O created in situ in mouse spleen is capable of being transported out of the spleen by the blood supply, (2) suggest that 13N may be 100% biologically mobile, and (3) indicate that 11C appears to be evenly divided between a population associated with small biologically mobile molecules and a population associated with larger, biologically trapped or immobile molecules.

Animals↗

'Repair' of fast-neutron and x-ray-induced damage to the permeabilities of red blood cells to sodium and potassium ions and its promotion by ghosts.

Damage to the permeability of red blood cells to Na+ and K+ caused by irradiation with fast neutrons or X-rays was investigated at different post-irradiation incubation temperatures. The extent of Na+ uptake and K+ loss by the cells after either radiation was higher at 4 degrees C than at 37 degrees C, but the extent of 'repair' of the damage caused by fast neutrons was lower than that caused by X-rays. The latter 'repair' was promoted by the addition of ghosts, but the former was not. On the other hand neither 'repair' process was influenced by haemolysates from which ghosts had been removed.

Animals↗