A comparison of clinical and laboratory data on neutron therapy for locally advanced tumors

Experimental results suggest advantages for neutrons where cells are hypoxic, in tumors which are slowly growing and also in a relative sparing of bone damage. The neutrons available at Hammersmith were of 7.5 MeV energy and produced a poorly penetrating beam, unsuitable for treating tumors in the pelvis and abdomen. Patients with locally advanced tumors in superficial sites were therefore selected to assess the effects of neutrons on normal and malignant tissues. One hundred and eight-nine patients had between them 191 locally advanced (T4 N0-3) tumors in the oral cavity, paranasal sinuses, salivary glands, and breast. Neutron therapy resulted in complete regression in 84% of which 13% subsequently recurred. Median survival for the whole group was 32 months. Twenty-eight other patients had advanced tumors of the head and neck which were recurrent after X ray therapy and other treatments; 82% of these completely regressed for more than 1 year. Complications appeared in 27% of patients not previously treated and in 46% who had already undergone X ray therapy. Seventy-four per cent of complications started in the skin. With neutrons of this energy there is minimal sparing of the skin and uneven distribution of dose resulting in "hot" spots. These affected skin, subcutis, and muscle. The high rates of control in these large tumors, the low incidence of bone necrosis, and the repair of some bones eroded by tumor correlate well with the experimental data. There was rapid regression of the tumor and close correlation between early and late effects on skin and subcutis. These two observations may relate to the fractionation, total dose, and overall time of treatment of 1560 cGy neutron dose given in 12 fractions over 28 days.     

RBE for lung and cord

The sparing effect of fractionation of neutron dose is very small for late damage in tissues. This is seen in the almost flat isoeffect curve for damage to skin, CNS and to lung. This means that differences in the RBE curves for these tissues are determined by differences in the slopes of the photon isoeffect curves. The relevant slopes of the photon isoeffect curves giving the exponent of N in the Ellis formula are 0.24 for subcutaneous tissue, 0.27 for lung damage and 0.38–0.45 for damage to spinal cord, while the exponent for N for neutrons for these tissues is 0.04 for subcutaneous tissues and zero for lung and spinal cord. The slopes of the RBE curves for lung and cord or for skin and cord when RBE is plotted against dose/fraction of photons are significantly different, and the RBE at a γ ray dose/fraction normally used in therapy of about 2 Gy, is significantly higher for spinal cord than for lung or skin. The sparing of damage by extending overall treatment time for both lung and CNS is small for X or γ-irradiation. For neutron irradiation the sparing is similar to that with photons for the CNS but is much less with neutrons than with photons for the lung. This is because different mechanisms are responsible for this type of sparing of damage in the two tissues. In lung slow, repair is involved while in the spinal cord, the sparing is related to the slow cell proliferation.     

The relative biological effectiveness of fast neutrons (42MeVd→Be) for early and late normal tissue injury in the pig

Early and late radiation damage has been investigated in a number of normal tissues in the pig after irradiation with single doses of neutrons produced by 42MeV deuterons on beryllium. The results have been compared with data obtained after irradiation with single doses of 250kV X rays. In the skin a low RBE value of approximately 1.2 was obtained for the early (3–9 week) epithelial reaction. For the subsequent dermal vascular response, higher RBE values in the range of 1.35–1.6 were obtained; the RBE decreasing with an increase in the neutron dose. For late skin damage, assessed by the relative reduction in the linear dimensions of an irradiated field, a RBE value of approximately 1.5 was obtained. In the kidney the RBE value, for a neutron dose level (550 ecy) at which renal function was just preserved, was 2.0. A lower value of 1.7 was found for doses resulting in a loss of renal function. The results of ¹³³Xenon clearance studies showed two waves of impaired ventilation function in the irradiated lung. In the acute reaction (3–9 months), at a dose level consistent with just preserving normal ventilation function, the RBE value was <1.2. For late lung damage (15–24 months) the R BE value was higher, 1.4. For the rectum, methods are presently only available for assessing acute damage. A RBE of 2.0 was found for neutron doses in the range 350–575 cGy. The RBE values for early endpoints in the skin, lung and gut of the pig are comparable with those published previously for other species, including man. The values for late effects in pig skin and lung were higher than for early damage in those tissues.     

Preclinical studies with the Faure high energy neutron facility: response of pig skin to fractionated doses of fast neutrons (66 MeVp----Be)

The early and late responses of pig skin to fractionated doses of both unfiltered and filtered (i.e. hardened) neutrons using the Faure neutron therapy facility (66 MeVp----Be) were determined and compared with those following fractionated doses with 60Co gamma-rays. Dose-effect curves for the quantal responses of moist desquamation (early epithelial response) and dermal necrosis (late response) were fitted by probit analysis and ED50 values obtained. For a neutron fractionation scheme comprised of 12 fractions in 26 days, and using an unfiltered beam, the ED50 values for moist desquamation and dermal necrosis were 18.67 +/- 2.22 and 22.25 +/- 0.48 Gy, respectively, whereas in the case of the filtered beam, the corresponding ED50 values were 24.78 +/- 1.44 and 23.30 +/- 0.47 Gy. In order to provide a comparison, the values for 24 fractions of 60Co gamma-rays given in 39 days (a clinical protocol used in the Groote Schuur Hospital) were 74.02 +/- 2.92 and 66.72 +/- 1.93 Gy for moist desquamation and dermal necrosis, respectively. For the unfiltered beam, values for the comparative biological effectiveness (CBE) were 3.96 and 3.00 for the early and late skin response, respectively. The corresponding CBE values were for the filtered beam 2.99 and 2.86. These results for the Faure neutron therapy facility can be extrapolated to the human situation with a high degree of confidence, so that the neutron dose which would yield acceptable skin damage in patients may be determined using the data presented here.     

Results of neutron therapy: differences,correlations and improvements

All machines that have given neutron therapy over the past 12 years are so unsatisfactory that they closely resemble the now obsolete X ray machines of the 1950's. Present day neutron machines increase complications and reduce the chance of giving adequate doses to tumors through mechanical deficiencies; these may dominate the biological effects of neutrons. Comparisons with modern megavoltage X rays in valid controlled clinical trials are impossible in most sites of the body, although such trials are being attempted. Despite the inadequacies of the neutron machines, most trials are showing no difference between the neutrons and X rays. The only completed trial of advanced tumors of the head and neck showed a significant advantage to the neutron-treated patients. Clinical data correlate closely with laboratory data from the MRC cyclotron at Hammersmith Hospital, London, where special treatment techniques have been developed and tumors are specially selected for neutron therapy. These correlations are seen in the lack of damage to normal bone (because of the low kerma of neutrons for bone), the lack of vomiting and the high rate of control of advanced tumors, presumably a result at the greater effect of neutrons on hypoxic cells. The Hammersmith dose is higher than that given in most other centers; this is possible because the special techniques used protect the normal tissues and deliver the dose as precisely as possible to the tumor. Where adenocarcinomas have been treated in superficial sites, a high rate of local control is achieved, but local control is significantly less when these tumors are deeply sited in the :abdomen and pelvis, presumably because of the impossibility of delivering an adequate dose from the low energy neutrons. Modern high energy cyclotrons are now available, and only when these machines treat patients adequately can the place of neutrons in the treatment of cancer be accurately assessed.     

Absence of a demonstrable gain factor for neutron beam therapy of epidermoid carcinoma of the head and neck

A comparison of normal tissue and tumor responses in patients treated with the high energy Fermilab neutron beam and conventional photons (Cobalt and 4 MeV X rays), yielded the following parameters. For neutrons the median dose for significant radiation injury in the irradiated tissues was 31 (±2) Gy and the median dose for local control of the tumor was 26 (±2) Gy. The corresponding doses for photons were 90 (±4) Gy for normal tissue injury and 74 (±3) Gy for local control of the tumor. These figures show that the therapeutic ratio is roughly 1.2 for both neutrons and photons. Similarly, the RBE of neutrons relative to photons is about the same for normal tissue tolerance and for tumor control. Under these conditions, there is no demonstrable therapeutic gain factor for neutrons relative to photons. The overall local control rate was the same for both modalities (44%).     

Early fractionation methods and the origins of the NSD concept

The concept of the time factor in radiotherapy originated in the controversy surrounding single-dose and fractionated treatments during the first 20 years of this century. The success of Coutard's fractionated treatments of larynx tumors was an important factor in the abandonment of single-dose treatments. There was considerable research afterwards into the influence of dose rate and overall time of treatment on the responses of normal tissues. Recovery was modeled in terms of the Schwarzschild law of photochemistry, as exemplified by the analysis of Strandqvist in log dose-log time coordinates. Different conventions were followed in defining the time for a single-dose treatment. Subsequently the concept arose that the slopes of isoeffect lines relating dose and treatment time for normal tissues and tumors were different and moreover that the effects of fraction number and overall time could be separated; these developments constituted the foundation of the Ellis NSD model. It had an important influence on clinical practice and was reasonably successful in predicting isoeffective regimens for acute effects. It failed to predict severe late effects after large dose fractions. The dissociation between acute and late effects with altered fractionation led to recognition of the importance of the ratio alpha/beta in characterizing the fractionation sensitivity of tissues.     

Late effects of fractionated pi-mesons compared to X rays on mouse lung

Early and late delayed effects of up to 20 fractions of pions and X rays were investigated in the mouse lung. The whole thorax of female CD-1 mice was irradiated under Ethrane/O2 anesthesia. Respiration rate was measured by whole body plethysmography at biweekly to monthly intervals. With signs of irreversible respiratory distress, animals were sacrificed and their lungs evaluated histologically. In addition to the effect of fractionation, the influence of dose-rate and anesthesia was studied as well. The degree of injury for the most predominant lesions (macrophage accumulation, fibrosis, vascular congestion) was scored, and the correlation with the relative change in respiratory rate and survival was analyzed. This analysis showed the primary lesion to be radiation pneumonitis at a median survival time of approximately 100 days. Focal fibrosis was observed to occur soon thereafter, and no evidence was obtained for an independent second wave of fibrotic injury. Fibrosis seemed primarily the result of pathological organization in areas with heavy concentration of macrophages. It was observed that the mice were unusually sensitive, with a single dose X ray ED50/180 of 8.8 Gy. A similar value was found for unanesthetized mice. This might have been the result of performing these studies at an altitude of 2100 m. The fractionation effect also seemed more pronounced, with alpha/beta values of 0.6 Gy for X rays and 4 Gy for pions, which is significantly lower compared to reported values. At the pion dose-rate of 0.25 Gy.min-1, RBE values for single doses were 0.9 when compared to high dose-rate X rays, and 1.36 at equivalent dose rates. This clearly shows that significant repair occurs during the relatively low dose-rate pion irradiations. With smaller doses per fraction, the dose-rate effect became less dominant, and for 20 fractions of pions the RBE was 1.4 compared to fractionated high dose-rate X rays. These RBE's are similar to values reported for acute effects in skin.     

An analysis of the radiation related morbidity observed in a randomized trial of neutron therapy for bladder cancer

This report is an analysis of the morbidity in the bladder and bowel observed in a randomized trial of d(15)+Be neutrons versus megavoltage photons in the treatment of bladder cancer. Acute reactions in the bladder and bowel were significantly worse after photon therapy. Of the patients treated with photons 45.7% had severe reactions in the bladder compared with 10.6% after neutron therapy (p less than 0.001). Severe acute bowel reactions were observed in 8.5% of the patients after photon therapy compared with 3.8% after neutron therapy (p less than 0.05). Late reactions were significantly worse after neutrons. Severe late reactions in the bladder were seen in 58.5% of patients after neutron therapy and in 40.5% after photon therapy (p less than 0.05). In the bowel they were observed in 53.3% of patients after neutron therapy compared with 8% after photon therapy (p less than 0.0001). The disparity in the degree of early and late complications makes assessment of RBE values difficult. It is estimated that for bladder morbidity the RBE value, for photon dose fractions of 2.75 Gy, is less than 3.3 for early reactions and equal to 3.4 for late effects. The respective RBE values for early and late effects in the bowel are less than 3.4 and 3.8.     

THE EARLY RESPONSE OF PIG SKIN TO FRACTIONATED DOSES OF 35 MeV P-Be FAST NEUTRONS IRRADIATION

The early responses of pig skin to fractionated doses of fast neutrons (35 Mev P→B) were determined. A neutron fractionation scheme comprised of 12 fractions in 42 days. The lowest doses of Ⅰ, Ⅱ, Ⅲ degree erythema of pig skin by Irradiation were 16. 38, 17. 32 and 19. 78 Gy respectively. The ED50 Values for moist desquamation was 23. 40 Gy. The mean latency of early pig skin damage was prolonged with the decreasing of total dose. The degree and the incidence of early pig skin damage were associated with total dose.These results for fast neutron therapy facility can be extrapolated to the human situation with a high degree of confidence, so that the neutron dose which would yield acceptable skin damage in patients may be determined using the data presented here.     

Experimental studies on the response of growing bones to X ray and neutron irradiation

The effects of X ray and 14 MeV neutron irradiation on growing tibia of mice were studied. As reported in the literature, the age of the animal at irradiation was an important factor if the endpoint in analyzing the radiation effect is the absolute shortening, difference in length between unirradiated and irradiated tibia, achieved by the treatment. However, if the growth remaining at the moment of irradiation is taken into account no significant differences in effect were observed with aging, and the dose given appeared to be the overruling factor. This was valid for both X ray and neutron irradiation. Absorbed dose-response curves after X ray irradiation showed a shoulder in the lower range of absorbed doses, which was not the case for neutron irradiation. RBE values for 14 MeV neutrons as compared to 250 kV X rays varied from 3.6 to 2.0 depending on the single absorbed dose level. No differences in RBE were found with aging. A mathematical formula was derived which can predict the absolute shortening when the initial and final length of the tibia are known as well as the absorbed dose of irradiation to be administered.     

Leg contracture in mice after single and multifractionated 137Cs exposure

This is a report of studies of time-dose relationships for post-irradiation leg contractures in mice. The isoeffect doses for various degrees of contracture, measured 250 days after irradiation, increased with the number of fractions, but not with the overall treatment times, throughout 30 days. The isoeffect curves relating the total doses for given levels of responses to the doses per fraction were steeper for leg contractures than for acute skin reactions. The alpha/beta ratios ranged from 1.4 to 5.0 Gy, depending on the degrees of contracture. They were less than the 7.5 to 50 Gy for acute skin reactions as determined in previous experiments using the same animals and irradiation systems. Thus, the data resembled those from other slowly-responding normal tissues such as the spinal cord, kidney and lung. The leg contracture consisted of dermatogenic, myogenic, and arthrogenic components; after the mice were sacrificed there was residual contracture following removal of the skin and muscle. Inhibition of bone growth accounted for only a small proportion of the contracture. The overall response reflected responses of several tissue types.     

The relationship between lung colony and in situ assays

The relationship between three different assays: tumor control, tumor growth delay and lung colony formation, was examined after fast neutron and gamma ray irradiations. Fibrosarcomas (NFSa) in syngeneic C3Hf mice were irradiated locally with 60Co gamma rays, fast neutrons or mixed beams (gamma rays and fast neutrons). A comparison between the lung colony assay and the TRT50 (50% tumor growth delay time) assay when cells were exposed to single doses of fast neutrons or gamma rays, resulted in identical growth delay times. The fraction of cells surviving a single dose of fast neutrons, was 10 times higher than the surviving fraction of cells after a single dose of gamma rays. Both doses resulted in the same tumor control probability (TCD50 assay). Neither repair of potentially lethal damage nor tumor bed effect was sufficient to explain the difference between cell survival and tumor control probability. The surviving fraction of cells following fractionated irradiations of gamma rays and fast neutrons were identical at 50% tumor control probabilities.     

The effects of fractionated doses of fast neutrons or photons on the canine brain: Evaluation by computerized tomography and evoked response recording

The use of fast neutrons in the treatment of cancer necessitates a knowledge of the normal tissue responses. This study was designed to compare the late effects of fractionated doses of fast neutrons with fractionated doses of photons on canine brains by evoked response recording and viewing computerized tomograms (CT). Adult male beagles were irradiated to the entire brain (four fractions per week) with fast neutrons to total doses of 13.33 Gy (1333 rad), 20 Gy (2000 rad), 30 Gy (3000 rad) or 45 Gy (4500 rad) or with photons (four fractions per week) to total doses of 40 Gy (4000 rad), 60 Gy (6000 rad) or 90 Gy (9000 rad). A relative biological effectiveness (RBE) of 4 was obtained for normal brain tissue assessed by mortality and onset of neurologic symptoms. Every three months post-irradiation, visual and sensory evoked responses were recorded. Changes over time appeared to be minimal; however, computerized tomographs showed marked brain shrinkage. A method of quantitating cerebrospinal fluid and parenchyma) volumes from scans is described and future use of these CT ratios to generate dose response curves and RBE values is postulated.     

Schedule-dependent therapeutic gain from the combination of fractionated irradiation plus c-DDP and 5-FU or plus c-DDP and cyclophosphamide in C3H/Km mouse model systems

Cytotoxic drugs were administered either in single or fractionated doses before, during, or after a standard course of 5 daily X ray exposures. SCCVII and RIF-1 tumors were grown from cells implanted in the gastrocnemius muscles of syngeneic C3H/Km mice, and treatments were evaluated by regrowth delay (GD). Non-tumor-bearing mice were irradiated locally to the upper abdomen for analysis of intestinal crypt cell survival, an acute normal tissue effect; other non-tumor-bearing mice were irradiated locally to the thorax for analysis of early (pneumonitis) and late (fibrosis) effects on the lungs, as reflected in changes in breathing rates. In a series of experiments to test the combination of i.p. 5-FU, cis-DDP, and X ray, dose effect factors (DEF's) were compared so that therapeutic gain factors (TGF's) could be calculated from the ratio, DEF (tumor)/DEF (normal tissue). The highest TGF, 6.7 (tumor/duodenum), was obtained for the schedule in which 100 mg/kg 5-FU was given 24 hr before the simultaneous administration of 1.6 mg/kg cis-DDP and X ray for 5 consecutive days. The following summary refers only to tumor growth delay data. In confirmation of previous extensive experiments, the combination of cis-DDP + X ray showed supra-additivity, whether the drug was given in a single dose (abbreviated P) or simultaneously with X ray (abbreviated px), that is, P x x x x x or px px px px px. For CY + X ray, the greatest supra-additivity was obtained for either C x x x x x or x x x x x C. 5-FU alone did not act supra-additively with fractionated irradiation, but the addition of 5-FU to cis-DDP + X ray was supra-additive for certain schedules, maximally for F px px px px px. CY combined to give greater than additivity with either cis-DDP or X ray alone, and the combination of CY + cis-DDP + X ray appeared to be supra-additive for five different schedules, maximally for C x x x x x P. Normal tissue effects are being evaluated for these same schedules so that TGF's might soon be obtained.     

Possible Alteration of the Blood-Brain Barrier by Boron-Neutron Capture Therapy

In the course of re-assessment of boron-neutron capture therapy (BNCT) for malignant brain tumors, fractionation of neutron irradiation has been proposed. the authors have used BNCT with a single fraction technique during the past 21 years and now decided to study some effects of fractionation. Twenty-two healthy mouse brains were irradiated with thermal neutrons after boron-10 injection (mercaptoundecahydrododecaborate). A second dose of boron-10 was administered and its uptake in the boron-neutron-capture-irradiated brains was determined. A tendency towards increased boron uptake in the moderately BNCT-treated brains was noticed, which may result in increased brain damage if fractionated neutron irradiation is used.     

Radiobiology of neutrons

Tumor responses depend on a number of factors, of which the intrinsic radiosensitivity of the cells and their oxygenation condition can be considered as most important. Variations of the sensitivity in the cell cycle and differences between resting and proliferating cells are considered to play a smaller part. Large differences in intrinsic cellular sensitivity and in RBE values of fast neutrons have been observed for impairment of the clonogenic capacity of cells in culture and in experimental tumors. For most of the treatments commonly applied in radiotherapy, doses per fraction are smaller than 5 Gy of photons and 1.5 Gy of neutrons. In these dose ranges, the survival curves of mammalian cells can be described by the formula: $\text{S(D)}\text{S(0)}\text{= exp ? (a}{}_1\text{D + a}{}_2\text{D}{}^2\text{)}$. Values of a, range between 10^?1 and 1 Gy^?1 for photons; they are a factor of 3 to 10 larger for fast neutrons, depending on the type of cell and the neutron energy spectrum. However, a direct correlation between cellular sensitivity and the magnitude of RBE values has not been established. The influence of fractionation is described by the value of $\text{a}{}_1\text{a}{}_2$. It is shown that for several important normal tissues these values are smaller than for cells from a number of experimental tumors. Therefore, with X rays, more sparing of normal tissues is obtained than for these tumors, and the application of neutrons is not expected to provide an advantage in this respect. The presence of hypoxic cells in experimental tumors has been well established. It has been observed, however, that for daily fractionated treatments with doses of less than 3 Gy of photons, the influence of hypoxia is much smaller than for single large doses, because of the process of reoxygenation. Nevertheless the low OER of fast neutrons and other high LET radiation might provide an advantage that could improve treatment results. It is suggested that better methods must be developed to predict the responsiveness of tumors in patients to photons, in order to selectively apply high LET radiations only to tumors that are resistant to photons.     

Studies of dose-fractionation on early and late responses in pig skin: a reappraisal of the importance of the overall treatment time and its effects on radiosensitization and incomplete repair

Studies in pig skin have examined the effects of dose fractionation on the acute radiation response. The variation in ED50 values for moist desquamation for doses given as 1-48 fractions over less than or equal to 16 days were best fitted by a log-log plot of iso-effect dose against the number of fractions; the slope of this plot indicated a fraction number exponent (N) of 0.42 +/- 0.007. Based on the assumptions made in applying the linear-quadratic (LQ) model, the alpha/beta ratio was found to decrease with decreasing per fraction: for doses given as 6-27 Gy per fractions the alpha/beta ratio was 8.74 +/- 0.48 Gy, whereas for doses of 2.55-6 Gy per fraction it was only 0.85 +/- 0.29 Gy. A simple approach to a time factor could not be used to calculate iso-effect doses for acute reactions in pig skin when treatment time was increased from less than or equal to 16 days to 28-39 days. This was due to the opposing effects of radiosensitization and repopulation when the cell cycle time of epidermal basal cells was shortened. For late dermal necrosis in pig skin, repair of sublethal damage was not completed in 24 hr. This finding has a significant effect on the interpretation of the results of fractionation studies using this late endpoint. Expressed in terms of a simple power-law function, there was a significant change in the fraction number exponent "N" from 0.43 +/- 0.007 to 0.37 +/- 0.006 for the complete and incomplete repair data, respectively. Many of the fractionation effects reported for acute and late damage to pig skin would appear to be in excellent agreement with those for human skin.     

Tolerance of the human spinal cord to high energy p(66)Be(49) neutrons

The risk of post irradiation myelopathy was evaluated in 76 patients followed for 1-5 years after neutron irradiation of the cervical and thoracic regions. No overt myelopathy was observed. Forty-six patients received doses (central cord dose) in excess of 10 Gy, 9 received doses in excess of 12 Gy, and 5 received doses between 13 and 17 Gy, all without any evidence of spinal cord injury. On careful questioning, a subjective transient neuropathy (a tingling sensation in one extremity) was reported by 6 patients, but this was apparently unrelated to dose. A review of available literature revealed a total of 14 patients with myelopathy, 13 of whom received doses in excess of 13 Gy delivered with relatively low energy neutrons generated by the deuteron + beryllium reaction. It is concluded from these studies that the tolerance limit for the human spinal cord irradiated with high energy [p(66)Be(49)] neutrons is close to 15 Gy, above which the risk of cord injury becomes significant. Central cord doses of 13 Gy or less appear to be well tolerated with little, if any, risk of myelopathy. These conclusions are valid for a treatment time of 4 weeks or more with two or more fractions per week (9 or more fractions). The RBE for the human spinal cord irradiated under the above conditions compared with conventionally fractionated photon therapy does not exceed 4.0.