Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.

BACKGROUND: Preoperative radiotherapy has been shown to decrease the local recurrence rate of patients with locally advanced rectal cancer. Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer and have radiosensitizing properties. Therefore, these drugs would be expected to improve effectiveness of preoperative radiotherapy in terms of local control and prevention of distant metastases. PATIENTS AND METHODS: Forty patients with rectal cancer (T3-T4 and/or N+) received radiotherapy (1.8 Gy, 5 days a week over 5 weeks, total dose 45 Gy, 3D conformational technique) in combination with intravenous oxaliplatin 50 mg/m2 once weekly for 5 weeks and oral capecitabine 825 mg/m2 twice daily on each day of radiation. Surgery was performed 6-8 weeks after completion of radiotherapy. The main end points were safety and efficacy as assessed by the pathological complete response (pCR). RESULTS: The most frequent grade 3/4 adverse event was diarrhea, occurring in 30% of patients. pCR was found in five (14%) patients. According to Dworak's classification, good regression was found in six (18%) additional patients. CONCLUSIONS: Combination of preoperative radiotherapy with capecitabine and oxaliplatin is feasible for downstaging rectal cancer.

Proton RBE for early intestinal tolerance in mice after fractionated irradiation.

BACKGROUND AND PURPOSE: To determine the influence of the number of fractions (or the dose per fraction) on the proton relative biological effectiveness (RBE). MATERIALS AND METHODS: Intestinal crypt regeneration in mice was used as the biological endpoint. RBE was determined relative to cobalt-60 gamma rays for irradiations in one, three and ten fractions separated by a time interval of 3.5h. Proton irradiations were performed at the middle of a 7-cm Spread Out Bragg Peak (SOBP). RESULTS: Proton RBEs (and corresponding gamma dose per fraction) at the level of 20 regenerated crypts per circumference were found equal to 1.15+/-0.04 (10.0 Gy), 1.15+/-0.05 (4.8 Gy) and 1.14+/-0.07 (1.7 Gy) for irradiations in one, three and ten fractions, respectively. Alpha/beta ratios as derived from direct analysis of the 'quantal radiation response data' were found to be 7.6 Gy for gamma rays and 8.2 Gy for protons. Additional proton irradiations in ten fractions at the end of the SOBP were found to be more effective than at the middle of the SOBP by a factor of 1.14 (1.05-1.23). CONCLUSION: Proton RBE for crypt regeneration was found to be independent of fractionation up to ten fractions. One can expect that it remains unchanged for higher number of fractions as the lethalities for doses smaller than 3 Gy are exclusively due to direct lethal events. As a tendency for increased effectiveness at the end of the SOBP is reported in the majority of the studies, for clinical applications it would be advisable to allow for by arranging a sloping depth dose curve in the deeper part of the target volume. Finally, it must be noticed that most of in vitro and in vivo RBE values for protons are larger than the current clinical RBE (RBE=1.10).

Protocol for X-ray dosimetry in radiobiology.

PURPOSE: To harmonize X-ray dosimetry in radiobiology to allow a direct comparison of radiobiological studies performed at institutes cooperating within the framework of the European Late Effects Project Group (EULEP). MATERIALS AND METHODS: The 1985 EULEP protocol for X-ray dosimetry and exposure arrangements employed for studies of late somatic effects in mammals required serious revision, e.g. due to the replacement of calibration of dosemeters in terms of exposure by calibration in terms of air kerma free-in-air. An action group established by EULEP and the European Radiation Dosimetry Group (EURADOS) updated the 1985 protocol. RESULTS: The new EULEP-EURADOS protocol for X-ray dosimetry in radiobiology including the code of practice for irradiation of small animals and related dosimetry. The present protocol includes the changes in calibration procedures and dosimetric concepts for irradiation with medium energy X-rays since 1985. Accuracy and precision are replaced by the concept of combined (standard) uncertainty. The revised supplements provide more detailed background information. New appendices contain definitions of general terms used for measurements and mathematical expressions of the relative variances. CONCLUSION: Adherence to the present protocol will result in improved dosimetry and facilitates the comparison of results of radiobiological experiments obtained at different institutes.

Comparison of setup accuracy of three different thermoplastic masks for the treatment of brain and head and neck tumors.

PURPOSE: Setup accuracy is an important factor influencing the definition of the planning target volume (PTV). The purpose of this study was to compare the setup accuracy of three different thermoplastic masks used for immobilization of patients with brain or head and neck tumors. MATERIALS AND METHODS: Thirty patients with brain or head and neck tumors were consecutively assigned to one of three different thermoplastic masks (Posifix): head mask with three fixation points (3 FP, ten patients), head and shoulder mask with four fixation points (4 FP, ten patients), head and shoulder mask with five fixation points (5 FP, four fixations plus an additional one on the top of head, ten patients). Once a week, during the session with a 6 MV linac (Elekta), orthogonal (antero-posterior and lateral) portal images were acquired for three fictitious isocenters placed during the simulation at the level of the head, the neck and the shoulders. Portal images and digitized simulator films were compared using the PIPS pro software, and displacements in antero-posterior (A-P), cranio-caudal (C-C) and medio-lateral (M-L) directions were calculated. From these displacements, 2D or 3D errors were also calculated. RESULTS: A total of 915 portal images were obtained, of which 98% could be analyzed. For the whole population, total displacements reached a standard deviation (SD) of 2.2 mm at the level of the head and the neck. Systematic and random displacements were in the same order of magnitude and reached a SD of 1.8 mm. Patient setup was slightly worse at the shoulder level with a total displacement of 2.8 mm (1 SD) for both the C-C and the M-L directions. There again, the systematic and the random components were in the same order of magnitude below 2.4 mm (+/-SD). For isocenters in the head and in the neck, there was no substantial difference in the setup deviation between the three masks. The setup reproducibility was found to be significantly worse (P=0.01) at the level of the shoulders with the 3 FP mask. For the 2D random error, 1 SD of 2.3 mm was observed compared to 0.8 and 1.2 mm for the 4 and 5 FP masks, respectively. Lastly, 90% of the 3D total deviations were below 4.5 mm for the head and the neck. In the shoulder region, 90% of the 2D total deviations were below 5.5 mm. CONCLUSION: Thermoplastic masks provide an accurate patient immobilization. At the shoulder level, setup variations are reduced when 4 or 5 FP masks are used. These data could be used for the assessment of margins for the PTV.

Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses.

PURPOSE: This study aims at providing relative biological effectiveness (RBE) data under reference conditions accounting for the determination of the "clinical RBE" of protons. METHODS AND MATERIALS: RBE (ref. (60)Co gamma-rays) of the 200 MeV clinical proton beam produced at the National Accelerator Centre (South Africa) was determined for lung tolerance assessed by survival after selective irradiation of the thorax in mice. Irradiations were performed in 1, 3, or 10 fractions separated by 12 h. Proton irradiations were performed at the middle of a 7-cm spread out Bragg peak (SOBP). Control gamma irradiations were randomized with proton irradiations and performed simultaneously. A total of 1008 mice was used, of which 96 were assessed for histopathology. RESULTS: RBEs derived from LD50 ratios were found not to vary significantly with fractionation (corresponding dose range, approximately 2-20 Gy). They, however, tend to increase with time and reach (mean of the RBEs for 1, 3 and 10 fractions) 1.00, 1.08, 1.14, and 1.25 for LD50 at 180, 210, 240, and 270 days, respectively (confidence interval approximately 20%). alpha/beta ratios for protons and gamma are very similar and average 2.3 (0.6-4.8) for the different endpoints. Additional irradiations in 10 fractions at the end of the SOBP were found slightly more effective ( approximately 6%) than at the middle of the SOBP. A control experiment for intestinal crypt regeneration in mice was randomized with the lung experiment and yielded an RBE of 1.14 +/- 0.03, i.e., the same value as obtained previously, which vouches for the reliability of the experimental procedure. CONCLUSION: There is no need to raise the clinical RBE of protons in consideration of the late tolerance of healthy tissues in the extent that RBE for lung tolerance was found not to vary with fractionation nor to differ significantly from those of the majority of early- and late-responding tissues.

Effect of gemcitabine on the tolerance of the lung to single-dose irradiation in C3H mice.

In an early phase II trial combining gemcitabine (dFdC) and radiotherapy for lung carcinomas, severe pulmonary toxicity was observed. In this framework, the objective of this study was to investigate the effect of dFdC on the tolerance of the lungs of C3H mice to single-dose irradiation. The thoraxes of C3H mice were irradiated with a graded single dose of 8 MV photons; dFdC (150 mg/kg) or saline (control animals) was administered i.p. 3 or 48 h prior to irradiation. Lung tolerance was assessed by the LD50 at 7-180 days after irradiation. For irradiation alone, the LD50 reached 14.45 Gy (95% CI 13.33-15.66 Gy). With a 3-h interval between administration of dFdC and irradiation, the LD50 reached 13.29 (95% CI 12.26-14.44 Gy); the corresponding value with a 48-h interval reached 13.01 Gy (95% CI 11.92-14.20 Gy). Our data also suggested a possible effect of dFdC on radiation-induced esophageal toxicity. dFdC has a minimal effect on lung tolerance after single-dose irradiation. However, a proper phase I-II trial should be designed before any routine use of combined dFdC and radiotherapy in the thoracic region.

The effect of 2'-2' difluorodeoxycytidine (dFdC, gemcitabine) on radiation-induced cell lethality in two human head and neck squamous carcinoma cell lines differing in intrinsic radiosensitivity.

PURPOSE: The present study investigated in vitro radio-enhancement by gemcitabine (dFdC) in two head and neck squamous cell carcinomas with different intrinsic cellular radiosensitivity. MATERIALS AND METHODS: Radiosensitive (SCC61, SF2=0.16) and radioresistant (SQD9, SF2=0.49) human head and neck squamous cell carcinomas were used. Confluent cells were incubated with dFdC and irradiated in drug-free medium with a single dose of 250 kV X-rays (0-12Gy). Cell survival curves were corrected for the toxicity of the drug alone. RESULTS: In both cell lines, radio-enhancement was observed with 5 microM dFdC incubated for 3 h prior to irradiation. Dose modification factors (DMF) at a surviving fraction level of 0.5 reached 1.3 (95% CI 1.1-1.6) and 1.5 (95% CI 1.4-1.5) for SQD9 and SCC61 cells, respectively. Radio-enhancement was associated with a modest increase in the alpha term of the linear-quadratic model. In SQD9 cells, radio-enhancement increased with dFdC incubation time. At 24h, DMF reached a value of 1.5 (95% CI 0.9-3.2). In SCC61 cells at 24h, DMF reached a value of 1.1 (95% CI 0.9-1.2). In both cell lines, radio-enhancement increased with dFdC concentration up to 5-10 microM from which values it levelled off up to 100 microM. CONCLUSIONS: The data indicated that dFdC induced a modest radio-enhancement in both cell lines. For a short incubation time, dFdC did not radio-enhance preferentially the more radio-resistant cells, whereas the opposite was observed for a longer time. In both cell lines, radio-enhancement was saturated above a dFdC concentration of 5-10 microM.

Comparison of external radiotherapy, laser microsurgery and partial laryngectomy for the treatment of T1N0M0 glottic carcinomas: a retrospective evaluation.

PURPOSE: The aim of this study was to retrospectively compare the efficacy and functional results of three treatment options for T1N0M0 glottic carcinomas applied in a single institution. MATERIALS AND METHODS: One hundred six charts of patients with biopsy-proven T1N0M0 glottic carcinomas treated between 1979 and 1995 were reviewed. There were 81 T1a and 25 T1b tumors. Forty-one patients were treated by radiotherapy (RT) (median dose of 64 Gy), 34 patients were treated by partial laryngectomy (PL) and 31 patients were treated by laser microsurgery (L) of which 10 received postoperative RT for positive margins. In 18 patients, a perceptual voice rating on a visual scale was performed by the patients themselves, three non-speech specialists and two speech therapists. RESULTS: With a median follow-up time of 63.5 months, the 5- and 10-year loco-regional control probabilities reached 91 and 87%, respectively, without any difference between the treatment groups. After salvage laryngectomy, the 5- and 10-year loco-regional control probabilities reached 97% without any difference between the treatment groups. For the whole population, overall survival reached 78 and 62.4% at 5 and 10 years, respectively. The actuarial incidence of second primary reached 19% at 10 years. Regarding the quality of voice, overall there was a trend towards a worse satisfaction index, more hoarseness and more breathiness after PL than after L or RT. CONCLUSIONS: Our data suggested that assuming proper selection of patients, RT and L yielded similar outcomes and functional results. Local recurrence can be adequately salvaged by surgery. On the other hand, PL appeared to yield similar loco-regional control probability but with a worse quality of voice.

Radiosensitization of mouse sarcoma cells by fludarabine (F-ara-A) or gemcitabine (dFdC), two nucleoside analogues, is not mediated by an increased induction or a repair inhibition of DNA double-strand breaks as measured by pulsed-field gel electrophoresis.

PURPOSE: To investigate the effect of fludarabine (F-ara-A) and gemcitabine (dFdC), two radiosensitizing nucleoside analogues, on the induction and repair of DNA dsb after ionizing radiation. MATERIALS AND METHODS: Radiosensitization of mouse sarcoma SA-NH and FSA cells was studied using a clonogenic assay. Cell survival curves were fitted with the linear-quadratic model. DNA dsbs were detected by pulsed-field gel electrophoresis under neutral conditions. RESULTS: F-ara-A (100 micromol dm(-3) for 1 h prior to irradiation) induced a substantial radiosensitization in SA-NH cells with a dose modification factor of 2.0 for a surviving fraction of 0.5. In a FSA mouse sarcoma cell line, dFdC (5 micromol dm(-3) for 3 h prior to irradiation) induced a modest radiosensitization with a DMF of 1.2 for a surviving fraction of 0.5. Under similar experimental conditions, neither F-ara-A nor dFdC altered the yield of radiation-induced DNA dsbs in the dose range of 0-40 Gy. After a single dose of 25 Gy (SA-NH cells) or 40 Gy (FSA cells), neither the kinetics of repair nor the amount of residual damage was affected by F-ara-A or dFdC. CONCLUSIONS: For experimental conditions under which radiosensitization was observed, neither the induction nor the repair of DNA dsbs after ionizing radiation were affected by F-ara-A or dFdC.

RBE variation as a function of depth in the 200-MeV proton beam produced at the National Accelerator Centre in Faure (South Africa).

BACKGROUND AND PURPOSE: Thorough knowledge of the RBE of clinical proton beams is indispensable for exploiting their full ballistic advantage. Therefore, the RBE of the 200-MeV clinical proton beam produced at the National Accelerator Centre of Faure (South Africa) was measured at different critical points of the depth-dose distribution. MATERIAL AND METHODS: RBEs were determined at the initial plateau of the unmodulated and modulated beam (depth in Perspex = 43.5 mm), and at the beginning, middle and end of a 7-cm spread-out Bragg peak (SOBP) (depths in Perspex = 144.5, 165.5 and 191.5 mm, respectively). The biological system was the regeneration of intestinal crypts in mice after irradiation with a single fraction. RESULTS: Using 60Co gamma-rays as the reference, the RBE values (for a gamma-dose of 14.38 Gy corresponding to 10 regenerated crypts) were found equal to 1.16 +/- 0.04, 1.10 +/- 0.03, 1.18 +/- 0.04, 1.12 +/- 0.03 and 1.23 +/- 0.03, respectively. At all depths, RBEs were found to increase slightly (about 4%) with decreasing dose, in the investigated dose range (12-17 Gy). No significant RBE variation with depth was observed, although RBEs in the SOBP were found to average a higher value (1.18 +/- 0.06) than in the entrance plateau (1.13 +/- 0.04). CONCLUSION: An RBE value slightly larger than the current value of 1.10 should be adopted for clinical application with a 200-MeV proton beam.

Kinetics of mouse jejunum radiosensitization by 2',2'-difluorodeoxycytidine (gemcitabine) and its relationship with pharmacodynamics of DNA synthesis inhibition and cell cycle redistribution in crypt cells.

Gemcitabine (dFdC), a deoxycitidine nucleoside analogue, inhibits DNA synthesis and repair of radiation-induced chromosome breaks in vitro, radiosensitizes various human and mouse cells in vitro and shows clinical activity in several tumours. Limited data are however available on the effect of dFdC on normal tissue radiotolerance and on factors associated with dFdC's radiosensitization in vivo. The purpose of this study was to determine the effect of dFdC on mouse jejunum radiosensitization and to investigate the kinetics of DNA synthesis inhibition and cell cycle redistribution in the jejunal crypts as surrogates of radiosensitization in vivo. For assessment of jejunum tolerance, the mice were irradiated on the whole body with 60Co gamma rays (3.5-18 Gy single dose) with or without prior administration of dFdC (150 mg kg-1). Jejunum tolerance was evaluated by the number of regenerated crypts per circumference at 86 h after irradiation. For pharmacodynamic studies, dFdC (150 or 600 mg kg-1) was given i.p. and jejunum was harvested at various times (0-48 h), preceded by a pulse BrdUrd labelling. Labelled cells were detected by immunohistochemistry on paraffin-embedded sections. DNA synthesis was inhibited within 3 h after dFdC administration. After an early wave of apoptosis (3-6 h), DNA synthesis recovered by 6 h, and crypt cells became synchronized. At 48 h, the labelling index returned almost to background level. At a level of 40 regenerated crypts, radiosensitization was observed for a 3 h time interval (dose modification factor of 1.3) and was associated with DNA synthesis inhibition, whereas a slight radioprotection was observed for a 48-h time interval (dose modification factor of 0.9) when DNA synthesis has reinitiated. In conclusion, dFdC altered the radioresponse of the mouse jejunum in a schedule-dependent fashion. Our data tend to support the hypothesis that DNA synthesis inhibition and cell cycle redistribution are surrogates for radiosensitization. More data points are however required before a definite conclusion can be drawn.

Measurements of radiobiological effectiveness in the 85 MeV proton beam produced at the cyclotron CYCLONE of Louvain-la-Neuve, Belgium.

The RBE of the 85 MeV proton beam produced at the cyclotron of Louvain-la-Neuve using 60Co gamma rays as the reference radiation was determined for survival of Chinese hamster ovary cells in vitro and for intestinal crypt regeneration in mice in vivo. Cell survival curves determined at different depths yielded, for a surviving fraction (SF) of 0.01, RBE values of 1.11 +/- 0.05 at the initial plateau of the unmodulated beam, 1.10 +/- 0.03 at the middle of a 0.5-cm spread-out Bragg peak (SOBP), 1.03 +/- 0.03 at the beginning of a 3-cm SOBP and 1.07 +/- 0.03 at the end of a 3-cm SOBP. The highest RBE values were obtained at the middle of the 0.5-cm SOBP and at the end of the 3-cm SOBP (RBE = 1.22 and 1.16, respectively, at SF = 0.5), although the variations are not statistically significant. Irradiations with 3-Gy fractions separated by an interval of 3.5 h yielded RBEs of 1.11 +/- 0.30 and 0.90 +/- 0.32 at the initial plateau and at the middle of the 0.5-cm SOBP, respectively. Irradiations of mice at the middle of the 3-cm SOBP yielded an RBE of 1.08 +/- 0.03 for 20 regenerated crypts at a proton dose of 12.3 Gy.

RBE variation between fast neutron beams as a function of energy. Intercomparison involving 7 neutrontherapy facilities.

In fast neutron therapy, the relative biological effectiveness (RBE) of a given beam varies to a large extent with the neutron energy spectrum. This spectrum depends primarily on the energy of the incident particles and on the nuclear reaction used for neutron production. However, it also depends on other factors which are specific to the local facility, eg, target, collimation system, etc. Therefore direct radiobiological intercomparisons are justified. The present paper reports the results of an intercomparison performed at seven neutrontherapy centres: Orléans, France (p(34)+Be), Riyadh, Saudi Arabia (p(26)+Be), Ghent, Belgium (d(14.5)+Be), Faure, South Africa (p(66)+Be), Detroit, USA (d(48)+Be), Nice, France (p(65)+Be) and Louvain-la-Neuve, Belgium (p(65)+Be). The selected radiobiological system was intestinal crypt regeneration in mice after single fraction irradiation. The observed RBE values (ref cobalt-60 gamma-rays) were 1.79 +/- 0.10, 1.84 +/- 0.07, 2.24 +/- 0.11, 1.55 +/- 0.04, 1.51 +/- 0.03, 1.50 +/- 0.04 and 1.52 +/- 0.04, respectively. When machine availability permitted, additional factors were studied: two vs one fraction (Ghent, Louvain-la-Neuve), dose rate (Detroit), influence of depth in phantom (Faure, Detroit, Nice, Louvain-la-Neuve). In addition, at Orléans and Ghent, RBEs were also determined for LD50 at 6 days after selective abdominal irradiation and were found to be equal to the RBEs for crypt regeneration. The radiobiological intercomparisons were always combined with direct dosimetric intercomparisons and, when possible in some centres, with microdosimetric investigations.

Neutron therapy of bladder carcinoma: can a high rate of severe complications be avoided in neutron therapy?

We reviewed retrospectively a series of 58 patients with deeply invasive bladder cancer treated with fast neutron therapy (p(65) + Be) in order to evaluate its tolerance and side effects. Patients were divided into three groups according to treatment technique. Patients of group A received whole pelvis irradiation up to 50 Gy photon equivalent followed by a boost to the bladder up to 57-66 Gy photon equivalent (40-56 days). Group B patients were treated by a split course regimen of 30 Gy photon equivalent on the whole pelvis at 3-4 weeks interval (66-108 days). Group C patients, not suitable for radical treatment, received only 40-54 Gy photon equivalent (26-70 days). The overall 5-year actuarial survival rate was 30% (SE 8%). As expected, T stage was a statistically significant prognostic factor. The overall local control rate reached 21% at 4 years. Acute and late side effects were minimal to moderate. These results suggest that high-energy neutron beam treatment is at least as effective as photon beam treatment for bladder carcinoma, without a higher incidence of major side effects.

Radiobiological intercomparison of p(45)+Be and p(65)+Be neutron beams for lung tolerance in mice after single and fractionated irradiation.

The lung tolerance in mice after single and fractionated irradiations with p(45)+Be and p(65)+Be neutrons produced at the isochronous cyclotron "CYCLONE" of Louvain-la-Neuve (Belgium) was studied. Cobalt-60 gamma rays were used for control irradiations. The end point was the dose which was lethal to 50% of the mice by 180 days (LD50/180). On a log-log plot, the slope (+/- SE) of the relationship between total isoeffect dose and fraction number decreases from 0.34 +/- 0.01 for gamma rays to 0.19 +/- 0.01 for p(65)+Be and 0.12 +/- 0.01 for p(45)+Be neutrons. The data have been analyzed using the linear-quadratic (LQ) model. The alpha/beta ratio (+95% confidence interval) increases from 5.3 (4.3-6.4) for gamma rays to 20.7 (16.7-24.9) for p(65)+Be and 37.9 (25.8-65.8) for p(45)+Be. The RBEs of neutrons relative to gamma rays were estimated from the LQ parameters, to 1.15 and 1.19 for a dose of 14 Gy gamma rays and 2.02 and 2.47 for a dose of 2 Gy gamma rays for p(65)+Be and p(45)+Be neutrons, respectively. The neutron RBE of the p(45)+Be relative to the p(65)+Be calculated from the ratio of their respective RBEs relative to gamma rays reaches 1.03 and 1.23 for doses of 14 and 2 Gy gamma-ray equivalent, respectively. These data are compared with other published data on lung tolerance after irradiation with lower-energy neutrons and with data obtained previously in our laboratory on mouse jejunum and Vicia faba.

Variation of RBE between p(75) + Be and d(50) + Be neutrons determined for chromosome aberrations in Allium cepa.

The RBE of p(75) + Be neutrons relative to d(50) + Be neutrons has been determined for chromosome aberrations induced in Allium cepa (onion) roots. Two biological criteria were selected: the average number of aberrations (mainly fragments) per cell in anaphase and telophase, and the percentage of aberration-free cells. The influence of sampling time (3 to 7 h incubation) between irradiation and fixation was investigated systematically. This factor did not significantly influence the results. The RBE values of p(75) + Be neutrons compared to those of d(50) + Be neutrons were 0.85 (0.79-0.91) and 0.87 (0.80-0.95) for the first and the second criteria, respectively. In previous experiments for the same beams, we found an RBE of 0.90 (0.86-0.94) for survival of V79 cells (D0 ratio), 0.96 (0.93-0.99) for the intestinal crypt cell system, and 0.83 (0.70-0.96) for Vicia faba growth delay.

Radiobiological intercomparisons of fast neutron beams used in therapy.

A research program was performed at Louvain-la-Neuve to systematically determine the RBE of fast neutrons for the growth inhibition in Vicia faba bean roots and for the regeneration of the intestinal crypts in mice. The following neutron beams were compared p(75) + Be, p(65) + Be, p(45) + Be, p(34) + Be, d(20) + Be, and d(50) + Be. The RBE-variation as a function of neutron energy is larger for the Vicia faba system than for the regeneration of the intestinal crypt cells. This can be related to the inherent differency of the biological systems, but also to the different dose ranges involved (0.33 to 0.56 Gy and 7.66 to 8.56 Gy, respectively). In the high energy range explored, defined by the reactions p(75) + Be to p(34) + Be RBE varies only between 0.92 and 1.28 for Vicia faba and 0.96 and 1.12 for crypt cells normalized to the p(65) + Be beam. By contrast the RBE at lower energy beams (d(20) + Be and d(14.5) + Be) reaches values between 1.5 and 1.6 Finally fractionation has shown to be likely more important at the high energy beams.

Early repair kinetics of intestine and lung in mice, after fast neutron and photon irradiation.

Early repair (Elkind repair) kinetics of an early and a late responding tissue after gamma and d(50) + Be neutron irradiation were compared in mice. LD50 at five days after abdominal irradiation and LD50 at 180 days after thoracic irradiation were chosen as biological endpoints to study intestinal and lung tolerance, respectively. Elkind repair is assessed from the additional dose Dr to reach LD50 when a single dose Ds is split into two equal fractions Di separated by time intervals "i" ranging from 0 to 24 hours (Dr = 2Di-Ds). Dr is greater for lung than for intestine after both gamma and neutron irradiations. Our data are consistent with an exponential early repair with an half-life (T 1/2) of 0.5 h for intestine and 1.5 to 2 h for lung.

[Relative biological effectiveness (RBE) of neutrons produced by 50 MeV deuterons and by 34, 45, 65 and 75 MeV protons]. / Efficacité biologique relative (EBR) des neutrons produits à partir de deutons de 50 MeV et de protons de 34, 45, 65 et 75 MeV.

RBE of p(34) + Be, p(45) + Be, p(65), + Be, p(75) + Be and d(50) + Be neutron beams produced at the cyclotron "Cyclone" of Louvain-la-Neuve were measured. The biological criterion was the regeneration of the crypts of the intestinal mucosa (50 regenerated crypts per circumference) after abdominal irradiation in mice. Taking the p(65) + Be neutrons as reference, RBE values were found equal to 1.12, 1.07, 1.00 (Ref.), 0.96 and 1.02 respectively. These results are consistent with those published for cell lethality in vitro. However, the RBE variation is smaller than this previously obtained in the laboratory for growth inhibition in Vicia faba.

[Early cell repair of the lung and the intestine in mice, after irradiation by fast neutrons and gamma rays]. / Réparation cellulaire précoce du poumon et de l'intestin, chez la souris, après irradiation par neutrons rapides et rayons gamma.

Lung tolerance is assessed from LD50 at 180 days after thoracic irradiation, in mice, with d(50) + Be neutrons and 60Co gamma rays. Early intestinal tolerance is assessed from LD50 at 7 days after abdominal irradiation. Additional dose (Dr) to reach LD50 when a single dose Ds is split into 2 equal fractions Di separated by different time intervals "i", is determined (Dr = 2Di - Ds), Dr is larger after gamma than after neutron irradiation, for lung and intestine. After thoracic irradiation with gamma rays, Dr reaches 3.36, 4.38, 5.12 and 5.37 Gy for "i" = 2, 6, 12 and 24 hours respectively; after neutron irradiation, Dr reaches 0.66, 0.9, 1.29, 1.95 and 1.50 Gy for "i" = 1, 2, 4, 12 and 24 hours. Dr is smaller for intestine; after abdominal irradiation with gamma rays, it reaches 1.99, 2.59, 2.74, 3.11, 3.34, 4.44 and 4.56 Gy for "i" = 1, 2, 3.5, 8, 12, 18 and 24 hours; after neutron irradiation, it reaches 0.13, 0.45, 0.42 and 1.33 Gy for "i" = 1.5, 3.5, 5.5 and 24 hours. After gamma irradiation, early repair is complete after 3.5 hours for intestine and needs 12 hours for lung.