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Purpose: The relative biological effectiveness (RBE) in the presence or absence of CHK2 was estimated at the Korean National Cancer Center Proton Therapy Center (NCCPTC)., Methods and Materials: The proton beam was fixed at 210 MeV with 6-cm spread-out Bragg peaks (SOBPs) because this is expected to be the most frequently used clinical setting. X-rays were obtained using a 6-MV conventional linear accelerator. The RBE was estimated from the survival of jejunal crypt in C3H/He and Chk2(-/-) mice., Results: The estimated RBEs of the NCCPTC at the middle of the SOBP were 1.10 and 1.05 in the presence and absence of CHK2, respectively. The doses that reduced the number of regenerated crypt per jejunal circumference to 20 (D(20)) in C3H/He mice were 14.8 Gy (95% confidence interval [CI], 13.7-15.9) for X-rays and 13.5 Gy (95% CI, 14.5-15.5) for protons. By contrast, the doses of D(20) in Chk2(-/-) mice were 15.7 Gy (95% CI, 15.0-16.4) and 14.9 Gy (95% CI, 14.0-15.8) for X-rays and protons, respectively., Conclusions: The RBE of the NCCPTC is clearly within the range of RBEs determined at other facilities and is consistent with the generic RBE value of 1.10 for 150- to 250-MeV beams. The mutation of Chk2 gave rise to radioresistance but exhibited similar RBE., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The RBE of the new MIT fission converter epithermal neutron capture therapy (NCT) beam has been determined using intestinal crypt regeneration in mice as the reference biological system. Female BALB/c mice were positioned separately at depths of 2.5 and 9.7 cm in a Lucite phantom where the measured total absorbed dose rates were 0.45 and 0.17 Gy/ min, respectively, and irradiated to the whole body with no boron present. The gamma-ray (low-LET) contributions to the total absorbed dose (low- + high-LET dose components) were 77% (2.5 cm) and 90% (9.7 cm), respectively. Control irradiations were performed with the same batch of animals using 6 MV photons at a dose rate of 0.83 Gy/min as the reference radiation. The data were consistent with there being a single RBE for each NCT beam relative to the reference 6 MV photon beam. Fitting the data according to the LQ model, the RBEs of the NCT beams were estimated as 1.50 +/- 0.04 and 1.03 +/- 0.03 at depths of 2.5 and 9.7 cm, respectively. An alternative parameterization of the LQ model considering the proportion of the high- and low-LET dose components yielded RBE values at a survival level corresponding to 20 crypts (16.7%) of 5.2 +/- 0.6 and 4.0 +/- 0.7 for the high-LET component (neutrons) at 2.5 and 9.7 cm, respectively. The two estimates are significantly different (P = 0.016). There was also some evidence to suggest that the shapes of the curves do differ somewhat for the different radiation sources. These discrepancies could be ascribed to differences in the mechanism of action, to dose-rate effects, or, more likely, to differential sampling of a more complex dose-response relationship.

Purpose: To determine the relative biologic effectiveness (RBE) of the Paul Scherrer Institute (PSI) scanning proton beam in reference conditions and to evaluate the influence of intestine motion on the proton dose homogeneity., Methods and Materials: First, RBE was determined for crypt regeneration in mice after irradiation in a single fraction. Irradiation was performed at the middle of a 7-cm spread out Bragg peak (SOBP; reference position), as well as in the proximal part of the plateau and at the distal end of the SOBP. Control gamma-irradiation was randomized with proton irradiation and performed simultaneously. Second, motion of mouse intestine was determined by radiographs after copper wire markers had been placed on the jejunum and intestinal wall., Results: Proton RBE (reference (60)Co gamma) was equal to 1.16 for irradiation at the middle of the SOBP and to 1.11 and 1.21 for irradiation in the initial plateau and end of the SOBP, respectively. The confidence intervals for these RBE values were much larger than those obtained in the other proton beams we have tested so far. They exceeded +/-0.20 (compared with the usual value of +/-0.07), which resulted from the unusually large dispersion of the individual proton data. The instantaneous positions of the mice intestines varied by +/-2 mm in the course of irradiation., Conclusion: The results of this study have shown that the RBE of the PSI proton beam is in total accordance with the RBE obtained at the other centers. This experiment has corroborated that proton RBE at the middle of the SOBP is slightly larger than the generic value of 1.10 and that there is a slight tendency for the RBE to increase close to the end of the SOBP. Also, excessive dispersion of individual proton data may be considered to result from intestine motion, taking into account that irradiation at the PSI is delivered dynamically by scanning the target volume with a pencil proton beam ("spot scanning"). Because 2-mm movements resulted in significant variations in local dose depositions, this should be considered for moving targets. Strategies to reduce this effect for the spot scanning technique have been developed at the PSI for radiotherapy of humans.

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).

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.

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.

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.

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.

We studied the different effects of 5 FU fractional doses before and after fractional irradiation on the intestinal syndrome. The results indicate that the more effective administration of 5 FU is one single dose per week 9 hours after the last irradiation in a two weeks schedule.

We have studied the different effects on the intestinal syndrome between the administration of fractional doses of 5-Fu before and after irradiation. There is no difference between the diverse modalities and we obtain the same result when the 5-Fu is administered, fractionated or not, before or after the irradiation.

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.

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.

The study of the different effects of 5 FU administration before and after fractional irradiation on the medullar syndrome show the importance of the schedule in the effectiveness of the administration of the gamma rays and the cytostatic. As for the intestinal syndrome, the best results were obtained when 5 FU is administrated in one single dose per week 9 hours after the fifth irradiation for a two weeks schedule.

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.

We have studied the recovery for mice bone marrow cells after fractionated irradiation of the whole body. The additional dose (Dr) to obtain a given biological effect if the irradiation is split in two equal subfractions (2 Di) separated by a short interval of time (i) is 40 rad per day when the interval of time between the two irradiations is lengthened of one day.

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.

We have studied the effect of 5-Fu in fractional doses on the medullar syndrome after a single whole body cobalt irradiation in mice. The bone marrow is not sensitive to the fractionation of 5-Fu and it is the single dose of 5-Fu injected 72 hours after the irradiation which is the most effective.