Three-dimensional MRI-based treatment planning approach for non-invasive ocular proton therapy.

PURPOSE: To develop a high-resolution three-dimensional (3D) magnetic resonance imaging (MRI)-based treatment planning approach for uveal melanomas (UM) in proton therapy. MATERIALS/METHODS: For eight patients with UM, a segmentation of the gross tumor volume (GTV) and organs-at-risk (OARs) was performed on T1- and T2-weighted 7 Tesla MRI image data to reconstruct the patient MR-eye. An extended contour was defined with a 2.5-mm isotropic margin derived from the GTV. A broad beam algorithm, which we have called πDose, was implemented to calculate relative proton absorbed doses to the ipsilateral OARs. Clinically favorable gazing angles of the treated eye were assessed by calculating a global weighted-sum objective function, which set penalties for OARs and extreme gazing angles. An optimizer, which we have named OPT'im-Eye-Tool, was developed to tune the parameters of the functions for sparing critical-OARs. RESULTS: In total, 441 gazing angles were simulated for every patient. Target coverage including margins was achieved in all the cases (V95%  > 95%). Over the whole gazing angles solutions space, maximum dose (Dmax ) to the optic nerve and the macula, and mean doses (Dmean ) to the lens, the ciliary body and the sclera were calculated. A forward optimization was applied by OPT'im-Eye-Tool in three different prioritizations: iso-weighted, optic nerve prioritized, and macula prioritized. In each, the function values were depicted in a selection tool to select the optimal gazing angle(s). For example, patient 4 had a T2 equatorial tumor. The optimization applied for the straight gazing angle resulted in objective function values of 0.46 (iso-weighted situation), 0.90 (optic nerve prioritization) and 0.08 (macula prioritization) demonstrating the impact of that angle in different clinical approaches. CONCLUSIONS: The feasibility and suitability of a 3D MRI-based treatment planning approach have been successfully tested on a cohort of eight patients diagnosed with UM. Moreover, a gaze-angle trade-off dose optimization with respect to OARs sparing has been developed. Further validation of the whole treatment process is the next step in the goal to achieve both a non-invasive and a personalized proton therapy treatment.

The Financial Impact on Reimbursement of Moderately Hypofractionated Postoperative Radiation Therapy for Breast Cancer: An International Consortium Report.

AIMS: Moderately hypofractionated breast irradiation has been evaluated in several prospective studies, resulting in wide acceptance of shorter treatment protocols for postoperative breast irradiation. Reimbursement for radiation therapy varies between private and public systems and between countries, impacting variably financial considerations in the use of hypofractionation. The aim of this study was to evaluate the financial impact of moderately hypofractionated breast irradiation by reimbursement system in different countries. MATERIALS AND METHODS: The study was designed by an international group of radiation oncologists. A web-questionnaire was distributed to representatives from each country. The participants were asked to involve the financial consultant at their institution. RESULTS: Data from 13 countries from all populated continents were collected (Europe: Denmark, France, Italy, the Netherlands, Spain, UK; North America: Canada, USA; South America: Brazil; Africa: South Africa; Oceania: Australia; Asia: Israel, Taiwan). Clinicians and/or departments in most of the countries surveyed (77%) receive remuneration based on the number of fractions delivered to the patient. The financial loss per patient estimated resulting from applying moderately hypofractionated breast irradiation instead of conventional fractionation ranged from 5-10% to 30-40%, depending on the healthcare provider. CONCLUSION: Although a generalised adoption of moderately hypofractionated breast irradiation would allow for a considerable reduction in social and economic burden, the financial loss for the healthcare providers induced by fee-for-service remuneration may be a factor in the slow uptake of these regimens. Therefore, fee-for-service reimbursement may not be preferable for radiation oncology. We propose that an alternative system of remuneration, such as bundled payments based on stage and diagnosis, may provide more value for all stakeholders.

Severe depression more common in patients with ductal carcinoma in situ than early-stage invasive breast cancer patients.

PURPOSE: Ductal carcinoma in situ (DCIS) is associated with an excellent prognosis; historical studies have shown similar levels of psychological distress in patients with DCIS and with early-stage invasive breast cancer (early-IBC). It is suggested that these results might have led to better patient education about prognosis after DCIS. This study reports the current levels of anxiety, depression, and health-related quality of life (HRQoL) in DCIS and early-IBC patients. METHODS: DCIS (n = 89) and early-IBC patients, T1-2N0, (n = 361) were selected from the UMBRELLA breast cancer cohort. Patient-reported outcomes were prospectively collected before the start of adjuvant radiotherapy (baseline) and at 3, 6, 12, 18, and 24 months thereafter. Mixed models were used to compare differences in levels of anxiety, depression, and HRQoL between DCIS and early-IBC patients. RESULTS: DCIS and early-IBC patients reported similar levels of anxiety, which were highest at baseline. Depression scores were comparable between groups, also after stratification by use of adjuvant chemotherapy. The proportion of patients reporting high-risk depression scores (i.e., Hospital Anxiety and Depression Sale score >8) was significantly higher among patients with DCIS at 6, 12 and 18 months, and this proportion increased over the first 18 months. Health-related quality of life was comparable between both groups. CONCLUSION: Severe depression scores are more common in DCIS patients, despite their excellent prognosis. These results suggest that further improvement of patient education and effective patient doctor communication about the prognostic differences between patients with DCIS and invasive breast cancer is still highly needed.

TUmor-volume to breast-volume RAtio for improving COSmetic results in breast cancer patients (TURACOS); a randomized controlled trial.

BACKGROUND: Cosmetic result following breast conserving surgery (BCS) for cancer influences quality of life and psychosocial functioning in breast cancer patients. A preoperative prediction of expected cosmetic result following BCS is not (yet) standard clinical practice and therefore the choice for either mastectomy or BCS is still subjective. Recently, we showed that tumour volume to breast volume ratio as well as tumour location in the breast are independent predictors of superior cosmetic result following BCS. Implementation of a prediction model including both factors, has not been studied in a prospective manner. This study aims to improve cosmetic outcome by implementation of a prediction model in the treatment decision making for breast cancer patients opting for BCS. METHODS/DESIGN: Multicentre, single-blinded, randomized controlled trial comparing standard preoperative work-up to a preoperative work-up with addition of the prediction model. Tumour volume to breast volume ratio and tumour location in the breast will be used to predict cosmetic outcome in invasive breast cancer patients opting for BCS. Three dimensional (3D)-ultrasonography will be used to measure the tumour volume to breast volume ratio needed for the prediction model. Sample size was estimated based on a 14% improvement in incidence of superior cosmetic result one year after BCS (71% in the control group versus 85% in the intervention group). Primarily cosmetic outcome will be evaluated by a 6-member independent panel. Secondary endpoints include; (1) patient reported outcome measured by BREAST-Q, EORTC-QLQ-C30/BR23 and EQ-5D-5 L (2) cosmetic outcome as assessed through the BCCT.core software, (3) radiation-induced reaction (4) surgical treatment performed, (5) pathological result and (6) cost-effectiveness. Follow-up data will be collected for 3 years after surgery or finishing radiotherapy. DISCUSSION: This randomized controlled trial examines the value of a preoperative prediction model for the treatment-decision making. It aims for a superior cosmetic result in breast cancer patients opting for BCS. We expect improvement of patients' quality of life and psychosocial functioning in a cost-effective way. TRIAL REGISTRATION: Prospectively registered, February 17th 2015, at 'Nederlands Trialregister - NTR4997 '.

Who Should Bear the Cost of Convenience? A Cost-effectiveness Analysis Comparing External Beam and Brachytherapy Radiotherapy Techniques for Early Stage Breast Cancer.

AIMS: Standard treatment for early breast cancer includes whole breast irradiation (WBI) after breast-conserving surgery. Recently, accelerated partial breast irradiation (APBI) has been proposed for well-selected patients. A cost and cost-effectiveness analysis was carried out comparing WBI with two APBI techniques. MATERIALS AND METHODS: An activity-based costing method was used to determine the treatment cost from a societal perspective of WBI, high dose rate brachytherapy (HDR) and permanent breast seed implants (PBSI). A Markov model comparing the three techniques was developed with downstream costs, utilities and probabilities adapted from the literature. Sensitivity analyses were carried out for a wide range of variables, including treatment costs, patient costs, utilities and probability of developing recurrences. RESULTS: Overall, HDR was the most expensive ($14 400), followed by PBSI ($8700), with WBI proving the least expensive ($6200). The least costly method to the health care system was WBI, whereas PBSI and HDR were less costly for the patient. Under cost-effectiveness analyses, downstream costs added about $10 000 to the total societal cost of the treatment. As the outcomes are very similar between techniques, WBI dominated under cost-effectiveness analyses. CONCLUSIONS: WBI was found to be the most cost-effective radiotherapy technique for early breast cancer. However, both APBI techniques were less costly to the patient. Although innovation may increase costs for the health care system it can provide cost savings for the patient in addition to convenience.

Dose heterogeneity correction for low-energy brachytherapy sources using dual-energy CT images.

Permanent seed implant brachytherapy is currently used for adjuvant radiotherapy of early stage prostate and breast cancer patients. The current standard for calculation of dose around brachytherapy sources is based on the AAPM TG-43 formalism, which generates the dose in a homogeneous water medium. Recently, AAPM TG-186 emphasized the importance of accounting for tissue heterogeneities. We have previously reported on a methodology where the absorbed dose in tissue can be obtained by multiplying the dose, calculated by the TG-43 formalism, by an inhomogeneity correction factor (ICF). In this work we make use of dual energy CT (DECT) images to extract ICF parameters. The advantage of DECT over conventional CT is that it eliminates the need for tissue segmentation as well as assignment of population based atomic compositions. DECT images of a heterogeneous phantom were acquired and the dose was calculated using both TG-43 and TG-43 [Formula: see text] formalisms. The results were compared to experimental measurements using Gafchromic films in the mid-plane of the phantom. For a seed implant configuration of 8 seeds spaced 1.5 cm apart in a cubic structure, the gamma passing score for 2%/2 mm criteria improved from 40.8% to 90.5% when ICF was applied to TG-43 dose distributions.

Tumor factors predictive of response to hypofractionated radiotherapy in a randomized trial following breast conserving therapy.

PURPOSE: To determine whether tumor grade, molecular subtype and hypoxia predict response to hypofractionated versus standard radiotherapy (RT) following breast-conserving surgery (BCS) for node-negative breast cancer in a randomized controlled trial (RCT). PATIENTS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor blocks were available on 989 of 1234 patients enrolled in the Hypofractionation Whole Breast Irradiation (HWBI) Trial. A central pathology review and assessment of tumor grade using the Nottingham grading system was carried out. Tumors were classified by molecular subtype as luminal A, luminal B, HER2 enriched, basal-like or unclassified using a six-biomarker panel; ER, PR, HER-2, Ki67, CK5/6 and EGFR. Tumors were also classified as hypoxic based on the expression of HIF1α, CAIX or GLUT-1. The primary end point was local recurrence (LR). RESULTS: Median follow-up was 12 years. In the multivariable Cox model, molecular subtype was the only factor predictive of LR, the 10-year cumulative incidence was 4.5% for luminal A and basal-like, 7.9% for luminal B and 16.9% for HER-2 enriched tumors (P < 0.01). Tumor grade, molecular subtype or hypoxia did not predict response to hypofractionation. CONCLUSIONS: In women enrolled in the HWBI trial following BCS tumor molecular subtype predicted LR. However tumor grade, molecular subtype and hypoxia did not predict response to hypofractionation suggesting that patients with node-negative breast tumors of all grades and molecular subtypes may be safely treated with hypofractionated RT regimens.

Age at diagnosis predicts local recurrence in women treated with breast-conserving surgery and postoperative radiation therapy for ductal carcinoma in situ: a population-based outcomes analysis.

PURPOSE: The main goal of treating ductal carcinoma in situ (dcis) is to prevent the development of invasive breast cancer. Most women are treated with breast-conserving surgery (bcs) and radiotherapy. Age at diagnosis may be a risk factor for recurrence, leading to concerns that additional treatment may be necessary for younger women. We report a population-based study of women with dcis treated with bcs and radiotherapy and an evaluation of the effect of age on local recurrence (lr). METHODS: All women diagnosed with dcis in Ontario from 1994 to 2003 were identified. Treatments and outcomes were collected through administrative databases and validated by chart review. Women treated with bcs and radiotherapy were included. Survival analyses were performed to evaluate the effect of age on outcomes. RESULTS: We identified 5752 cases of dcis; 1607 women received bcs and radiotherapy. The median follow-up was 10.0 years. The 10-year cumulative lr rate was 27% for women younger than 45 years, 14% for women 45-50 years, and 11% for women more than 50 years of age (p < 0.0001). The 10-year cumulative invasive lr rate was 22% for women younger than 45 years, 10% for women 45-50 years, and 7% for women more than 50 years of age (p < 0.0001). On multivariate analyses, young age (<45 years) was significantly associated with lr and invasive lr [hazard ratio (hr) for lr: 2.6; 95% confidence interval (ci): 1.9 to 3.7; p < 0.0001; hr for invasive lr: 3.0; 95% ci: 2.0 to 4.4; p < 0.0001]. An age of 45-50 years was also significantly associated with invasive lr (hr: 1.6; 95% ci: 1.0 to 2.4; p = 0.04). CONCLUSIONS: Age at diagnosis is a strong predictor of lr in women with dcis after treatment with bcs and radiotherapy.

A Monte Carlo-based model of gold nanoparticle radiosensitization accounting for increased radiobiological effectiveness.

Radiosensitization using gold nanoparticles (AuNPs) has been shown to vary widely with cell line, irradiation energy, AuNP size, concentration and intracellular localization. We developed a Monte Carlo-based AuNP radiosensitization predictive model (ARP), which takes into account the detailed energy deposition at the nano-scale. This model was compared to experimental cell survival and macroscopic dose enhancement predictions. PC-3 prostate cancer cell survival was characterized after irradiation using a 300 kVp photon source with and without AuNPs present in the cell culture media. Detailed Monte Carlo simulations were conducted, producing individual tracks of photoelectric products escaping AuNPs and energy deposition was scored in nano-scale voxels in a model cell nucleus. Cell survival in our predictive model was calculated by integrating the radiation induced lethal event density over the nucleus volume. Experimental AuNP radiosensitization was observed with a sensitizer enhancement ratio (SER) of 1.21 ± 0.13. SERs estimated using the ARP model and the macroscopic enhancement model were 1.20 ± 0.12 and 1.07 ± 0.10 respectively. In the hypothetical case of AuNPs localized within the nucleus, the ARP model predicted a SER of 1.29 ± 0.13, demonstrating the influence of AuNP intracellular localization on radiosensitization.

Accuracy and completeness of pathology reporting--impact on partial breast irradiation eligibility.

AIMS: Accelerated partial breast irradiation (APBI) is an alternative to whole breast irradiation that is delivered over a shorter period of time with less toxicity. Appropriate patient selection is critical to its success and the American Society for Radiation Oncology (ASTRO) has published detailed selection criteria for 'suitable' patients. This study evaluated the effect of those selection criteria on APBI eligibility based on pathology reports. MATERIALS AND METHODS: From March 2004 to March 2007 all patients referred to a single cancer centre for breast radiotherapy were screened for participation in a phase I/II trial of permanent breast seed implant brachytherapy. Eligible patients underwent a computed tomography simulation and those referred from an outside institution had a secondary expert breast pathology assessment. Initial and expert pathology reports were compared regarding completeness and accuracy. RESULTS: In total, 143 patients were eligible for the trial; 79 patients had surgery carried out outside our institution. In the initial pathology report, the most frequently missing critical information was the resection margin width (29.1%) and the presence of extensive in situ carcinoma (11.4%). Comparing initial and reviewed pathology, the agreement was higher than 90% for most features. The main source of disagreement was the width of the negative resection margin, with 34.4% disagreement (P=0.016), although it changed eligibility in only 3.6%. There was major disagreement in the evaluation of lymphovascular invasion. Overall, pathology review changed the eligibility for a patient from 'suitable' for APBI to 'cautionary' in 18.6% of the cases. CONCLUSION: Using stringent eligibility criteria has a direct effect on patient screening for APBI. The use of synoptic pathology reporting and a quality assurance programme with secondary expert assessments are recommended.

Implications on clinical scenario of gold nanoparticle radiosensitization in regards to photon energy, nanoparticle size, concentration and location.

Gold nanoparticle (AuNP) radiosensitization represents a novel approach to enhance the effectiveness of ionizing radiation. Its efficiency varies widely with photon source energy and AuNP size, concentration, and intracellular localization. In this Monte Carlo study we explored the effects of those parameters to define the optimal clinical use of AuNPs. Photon sources included (103)Pd and (125)I brachytherapy seeds; (169)Yb, (192)Ir high dose rate sources, and external beam sources 300 kVp and 6 MV. AuNP sizes were 1.9, 5, 30, and 100 nm. We observed a 10(3) increase in the rate of photoelectric absorption using (125)I compared to 6 MV. For a (125)I source, to double the dose requires concentrations of 5.33-6.26 mg g(-1) of Au or 7.10 × 10(4) 30 nm AuNPs per tumor cell. For 6 MV, concentrations of 1560-1760 mg g(-1) or 2.17 × 10(7) 30 nm AuNPs per cell are needed, which is not clinically achievable. Examining the proportion of energy transferred to escaping particles or internally absorbed in the nanoparticle suggests two clinical strategies: the first uses photon energies below the k-edge and takes advantage of the extremely localized Auger cascade. It requires small AuNPs conjugated to tumor targeted moieties and nuclear localizing sequences. The second, using photon sources above the k-edge, requires a higher gold concentration in the tumor region. In this approach, energy deposited by photoelectrons is the main contribution to radiosensitization; AuNP size and cellular localization are less relevant.

Monte Carlo study of LDR seed dosimetry with an application in a clinical brachytherapy breast implant.

A Monte Carlo (MC) study was carried out to evaluate the effects of the interseed attenuation and the tissue composition for two models of 125I low dose rate (LDR) brachytherapy seeds (Medi-Physics 6711, IBt InterSource) in a permanent breast implant. The effect of the tissue composition was investigated because the breast localization presents heterogeneities such as glandular and adipose tissue surrounded by air, lungs, and ribs. The absolute MC dose calculations were benchmarked by comparison to the absolute dose obtained from experimental results. Before modeling a clinical case of an implant in heterogeneous breast, the effects of the tissue composition and the interseed attenuation were studied in homogeneous phantoms. To investigate the tissue composition effect, the dose along the transverse axis of the two seed models were calculated and compared in different materials. For each seed model, three seeds sharing the same transverse axis were simulated to evaluate the interseed effect in water as a function of the distance from the seed. A clinical study of a permanent breast 125I implant for a single patient was carried out using four dose calculation techniques: (1) A TG-43 based calculation, (2) a full MC simulation with realistic tissues and seed models, (3) a MC simulation in water and modeled seeds, and (4) a MC simulation without modeling the seed geometry but with realistic tissues. In the latter, a phase space file corresponding to the particles emitted from the external surface of the seed is used at each seed location. The results were compared by calculating the relevant clinical metrics V85, V100, and V200 for this kind of treatment in the target. D90 and D50 were also determined to evaluate the differences in dose and compare the results to the studies published for permanent prostate seed implants in literature. The experimental results are in agreement with the MC absolute doses (within 5% for EBT Gafchromic film and within 7% for TLD-100). Important differences between the dose along the transverse axis of the seed in water and in adipose tissue are obtained (10% at 3.5 cm). The comparisons between the full MC and the TG-43 calculations show that there are no significant differences for V85 and V100. For V200, 8.4% difference is found coming mainly from the tissue composition effect. Larger differences (about 10.5% for the model 6711 seed and about 13% for the InterSource125) are determined for D90 and D50. These differences depend on the composition of the breast tissue modeled in the simulation. A variation in percentage by mass of the mammary gland and adipose tissue can cause important differences in the clinical dose metrics V200, D90, and D50. Even if the authors can conclude that clinically, the differences in V85, V100, and V200 are acceptable in comparison to the large variation in dose in the treated volume, this work demonstrates that the development of a MC treatment planning system for LDR brachytherapy will improve the dose determination in the treated region and consequently the dose-outcome relationship, especially for the skin toxicity.

Sci-Sat AM(2): Brachy-05: Dosimetry effects of the TG-43 approximations for two iodine seeds in LDR brachytherapy.

PURPOSES: This work consists of studying the interseed and tissue composition effects for two model iodine seeds: the IBt Interseed-125 and the 6711 model seed. MATERIALS & METHODS: Three seeds were modeled with the MCNP MC code in a water sphere to evaluate the interseed effect. The dose calculated at different distances from the centre was compared to the dose summed when the seeds were simulated separately. The tissue composition effect was studied calculating the radial dose function for different tissues. Before carrying out post-implant studies, the absolute dose calculated by MC was compared to experiment results: with LiF TLDs in an acrylic breast phantom and with an EBT Gafchromic film placed in a water tank. Afterwards, the TG-43 approximation effects were studied for a prostate and breast post-implant. RESULTS AND DISCUSSION: The interseed effect study shows that this effect is more important for model 6711 (15%) than for IBt (10%) due to the silver rod in 6711. For both seed models the variations of the radial dose function as a function of the tissue composition are quasi similar. The absolute dose comparisons between MC calculations and experiments give good agreement (inferior to 3% in general). For the prostate and breast post-implant studies, a 10% difference between MC calculations and the TG-43 is found for both models of seeds. CONCLUSION: This study shows that the differences in dose distributions between TG43 and MC are quite similar for the two models of seeds and are about 10% for the studied post-implant treatments.

Sci-Thurs PM: Delivery-03: Optical imaging of microscopic radiation dose gradients using a digital microscope.

Using superior localization and immobilization methods, stereotactic radiosurgery is capable of delivering spheres of dose as small as a few millimetres in diameter to intracranial targets. For targets abutting critical structures, the most conformal treatments minimize adverse radiation side effects and it is important, therefore, to ensure proper quality assurance prior to delivering high doses of radiation to eloquent brain locations in a single fraction. This work examines the capability of a digital microscope, with translation stage and associated software, to resolve dose gradients in Gafchromic EBT™ film at the micron level. In order to validate the microscope-film system from a radiation physics approach, films were irradiated to produce very steep penumbrae by using very small fields, lower photon energies and minimal geometric penumbra contribution. Orthovoltage film irradiations were done by placing films in phantom beneath pinhole collimators. The experimentally determined off-axis dose profiles were compared with Monte Carlo computer simulations which replicated the irradiation geometry and served to validate our measured data. The measured 80% - 20% penumbral widths were 46 µm ± 26 µm (100 kVp, 2 mm field size) and 69 µm ± 27 µm (300 kVp, 2 mm field size). In the energy range covered, the measured penumbral widths agreed with Monte Carlo computer simulations within experimental uncertainty. The effects of noise originating from both the film and the microscope system are discussed and improvements to this system suggested.

Variability in radiation oncologists' opinion on the indication of a bolus in post-mastectomy radiotherapy: an international survey.

AIMS: Post-mastectomy radiotherapy (PMRT) decreases locoregional recurrence and increases survival for women with large tumours and/or node-positive disease. The American Society of Clinical Oncology has published treatment guidelines, but has also indicated that the optimal technique for PMRT remains unknown. The objective of this study was to evaluate the variability in which a bolus is currently used in PMRT and to identify the clinical situations in which a bolus is used. MATERIALS AND METHODS: In 2004, an e-mail survey was sent to all active physician members of the American Society for Therapeutic Radiology and Oncology, the Canadian Association of Radiation Oncologists and the European Society for Therapeutic Radiology and Oncology. The survey focused on the technical details regarding the use of a bolus in PMRT. RESULTS: In total, 1035 responses were obtained: 642 from the Americas (568 from the USA), 327 from Europe and 66 from Australasia. Respondents from the Americas were significantly more likely to always use a bolus (82%) than the Europeans (31%), as were the Australasians (65%) (P < 0.0001). Europeans were significantly more likely to use a bolus for specific indications (P < 0.0001). The results also showed wide variation in the schedule of application (every day [33%] and alternate days [46%]) and thickness used (< 1 cm [35%] and > or = 1 cm [48%]). CONCLUSIONS: There is a wide variation in the use of a bolus in PMRT with significant regional differences. This probably translates into a variation in the dose delivered to the skin and may have an effect on local recurrence and/or toxicity. A randomised clinical trial is needed to evaluate the benefit and toxicity associated with the use of a bolus in PMRT.

Radiotherapy for a solitary brain metastasis during pregnancy: a method for reducing fetal dose.

A patient presented during the second half of pregnancy with a solitary brain metastasis from lung cancer. This case shows that, using a new patient position, it is possible to shield the fetus efficiently. This new method consisted of whole brain irradiation with parallel pair treatment by lateral fields with the patient in a supine position with maximal neck extension. The dose to the fetus has been considerably reduced (0.3 cGy total dose) compared with previous techniques. The prescribed tumour dose was 30 Gy.

Recoil proton, alpha particle, and heavy ion impacts on microdosimetry and RBE of fast neutrons: analysis of kerma spectra calculated by Monte Carlo simulation.

Fast neutrons (FN) have a higher radio-biological effectiveness (RBE) compared with photons, however the mechanism of this increase remains a controversial issue. RBE variations are seen among various FN facilities and at the same facility when different tissue depths or thicknesses of hardening filters are used. These variations lead to uncertainties in dose reporting as well as in the comparisons of clinical results. Besides radiobiology and microdosimetry, another powerful method for the characterization of FN beams is the calculation of total proton and heavy ion kerma spectra. FLUKA and MCNP Monte Carlo code were used to simulate these kerma spectra following a set of microdosimetry measurements performed at the National Accelerator Centre. The calculated spectra confirmed major classical statements: RBE increase is linked to both slow energy protons and alpha particles yielded by (n,alpha) reactions on carbon and oxygen nuclei. The slow energy protons are produced by neutrons having an energy between 10 keV and 10 MeV, while the alpha particles are produced by neutrons having an energy between 10 keV and 15 MeV. Looking at the heavy ion kerma from <15 MeV and the proton kerma from neutrons <10 MeV, it is possible to anticipate y* and RBE trends.

[Alternating chemotherapy and hyperfractionated accelerated radiotherapy in non-metastatic inflammatory breast cancer]. / Radiothérapie hyperfractionnée accélérée alternée avec une chimiothérapie dans le cancer du sein inflammatoire non métastatique.

PURPOSE: Based on encouraging results reported in alternating radiotherapy and chemotherapy in inflammatory breast carcinoma, we have tried in this study to optimize locoregional treatment with a hyperfractionated accelerated radiotherapy schedule alternating with chemotherapy. PATIENTS AND METHODS: From May 1991 to May 1995, 54 patients, previously untreated, with non-metastatic inflammatory breast cancer were entered in an alternating protocol consisting of eight courses of combined chemotherapy and two series of loco-regional hyperfractionated accelerated radiotherapy with a total dose of 66 Gy. Hyperfractionated accelerated radiotherapy was started after three courses of neoadjuvant chemotherapy (Adriamycin, Vincristine, Cyclophosphamide, Methotrexate, 5-fluoro-uracile) administered every 21 days +/- G.CSF. The first series delivered 45 Gy/three weeks to the breast, the axillary, subclavicular and internal mammary nodes, with two daily sessions of 1.5 Gy separated by an interval of eight hours; the second series consisted of a boost (21 Gy/14 fractions/10 d) alternating with another regimen of anthracycline-based-chemotherapy (a total of five cycles every three weeks). Hormonal treatment was given to all patients. RESULTS: Of the 53 patients evaluated at the end of the treatment, 44 (83%) had a complete clinical response, seven (13%) had a partial response (> 50%) and two (4%) had tumoral progression. Of the 51 patients who were locally controlled, 18 (35%) presented a locoregional recurrence (LRR); eight (15%) had to undergo a mastectomy. All the patients but two with LRR developed metastases or died of local progressive disease and 26 (50%) developed metastases. With a median follow-up of 39 months (range: 4-74 months), survival rates at three and five years were respectively, 66 and 45% for overall survival and 45 and 36% for disease-free survival. CONCLUSION: Alternating a combination of chemotherapy and hyperfractionated accelerated radiotherapy is a well-tolerated regimen which provides acceptable local control. The systemic dissemination remains the major problem of inflammatory breast carcinoma and further clinical trials using alternative drug regimens are warranted.

[Radiotherapy of high grade glioma: use of fast neutrons, therapy and enhancement by neutron capture]. / Radiothérapie des gliomes de haut grade. Utilisation des neutrons rapides, therapie et potentialisation par capture de neutrons.

Among high linear energy transfer (LET) irradiations techniques, those using fast neutrons are able to eradicate glioblastoma cells. At least a 13 grays (Gy) irradiation dose has to be used, but high morbidity is observed in case of over 11 Gy irradiation. So, no therapeutic windows have been found despite the fact that more than 900 patients were included in clinical trials. Boron neutron capture therapy (BNCT) uses alpha emitting nuclear reactions, produced within tumoral cells by boron neutron captures. (10)B is specifically loaded inside tumoral cells via a boronated molecule, and the tissues are then irradiated with thermal or epithermal neutrons. Although this type of irradiation is yet considered as a regular method in Japan, USA and Europe have started clinical trials, currently in progress, in order to define the BNCT place in the post-operative care of high grade glioma. Non-removable tumors may benefit from boron neutron capture enhancement of fast neutron irradiation, i.e. the combination of these two methods. Preliminary studies show that a "biological" dose enhancement of 20 % could be obtained within the tumor when a concentration of 100 microg/g of (10)B is targeted into it. These concentrations are achievable by intra-arterial administration of (10)boronophenylalanine (BPA) or borosulfhydryl (BSH). Recently, some publications have also demonstrated that the thermal neutron flux yielded within the irradiated tissues could be increased. Clinical trials, using this technique, are planned in USA and Europe.