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In radiotherapy, the dose prescription is currently based on discretized dose-effects records that do not take into fully account for the complexity of the patient-dose-response relationship. Their predictive performance on both anti-tumour efficacy and toxicity can be optimized by integrating radiobiological models. It is with this in mind that the calculation models TCP (Tumor Control Probability) and NTCP (Normal Tissue Complication Probability) have been developed. Their construction involves several important steps that are necessary and important to understand. The first step is based on radiobiological models allowing to calculate according to more or less complexity the rate of surviving cells after irradiation. Two additional steps are required to convert the physical dose into an equivalent biological dose, in particular a 2Gy equivalent biological dose (EQD2): first to take into account the effect of the fractionation of the dose for both the target volume and the organs at risk; second to convert an heterogeneous dose to an organ into an homogeneous dose having the same effect (Niemierko generalized equivalent uniform dose (gEUD)). Finally, the process of predicting clinical effects based on radiobiological models transform doses into tumour control (TCP) or toxicity (NTCP) probabilities using parameters that reflect the radiobiological characteristics of the tissues in question. The use of these models in current practice is still limited, but since the radiotherapy softwares increasingly integrate them, it is important to know the principle and limits of application of these models., (Copyright © 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Adjuvant radiotherapy is a key treatment in early-stage breast cancer. The meta-analysis by the Early Breast Cancer Trialist's Collaborative Group (EBCTCG) has demonstrated a decreased risk of locoregional relapse and death after whole-breast radiotherapy. Prophylactic lymph nodes irradiation in breast cancer has also proven to be beneficial in several therapeutic trials. At a time when three-dimensional conformal radiotherapy has become the standard procedure and with the development of intensity-modulated radiation therapy, defining nodal volumes is essential and practices should be harmonized to assess and compare the efficiency and toxicity of radiotherapy. Furthermore, the indication of lymph nodes irradiation has to take into account the risk/benefit balance as expanding the irradiated volume can increase radio-induced toxicity. Selection of patients receiving this treatment is essential. The aim of this update is to define nodal volumes, to precise the indications of their irradiation and to present the expected benefits as well as the potential side effects., (Copyright © 2019 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Cancer caregivers are at high risk of burn-out, with potential severe consequences on professionals' health and on patients' care. We have investigated the prevalence of burn-out and its impact in terms of psychological morbidity among French radiation oncologists., Methods and Materials: An anonymous online questionnaire was advertised in all French senior radiation oncologists and residents, including demographical data, job-related stress factors, drug use, the Maslach Burn-out Inventory (MBI) and the General Health Questionnaire (GHQ-12)., Results: The response rates were 37% (76 out of 204) for radiation oncologists and 22% (166 out of 751) for residents. Sixty-four (84%) radiation oncology residents and 104 (63%) radiation oncologists met criteria for moderate/severe burn-out (odd ratio 2.1 [95% confidence interval 1.0-4.8], P=0.03). Radiation oncology residents were more prone to depersonalization (P<0.001) and lower personal accomplishment (P<0.001). Burn-out was more frequent in radiation oncologists working for public facilities. Symptoms of depression (GHQ-12≥4) were reported by 42% of residents and 36% of radiation oncologists (P=0.40). Psychological morbidity, suicidal ideation and anxiolytic consumption were more frequent in burnt out responders., Conclusion: Our figures are in the highest range of published data. Active screening and prevention of burn-out should be implemented and particularly aimed at radiation oncology residents., (Copyright © 2018 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Thymic epithelial tumors (TETs) are rare intrathoracic malignancies for which surgery represents the mainstay of the treatment. Current practice for postoperative radiotherapy (PORT) is highly variable, and there is a lack of prospective, high level evidence. Réseau Tumeurs Thymiques et Cancer (RYTHMIC) is the nationwide network for TETs in France. Established in 2012, it prospectively collects data on all TET patients, for whom management is discussed at a national multidisciplinary tumor board (MTB). We assessed whether PORT decisions at the MTB were in accordance with RYTHMIC guidelines and ultimately implemented in patients., Methods: All consecutive patients for whom PORT was discussed at the MTB from 2012 to 2015 were identified from the RYTHMIC prospective database, and a complete review of their medical records was performed., Results: A total of 274 patients, including 243 with thymoma (89%) and 31 with thymic carcinoma (11%), were analyzed. The decision of the MTB was in accordance with guidelines in 221 patients (92%) of the 241 with stage I or III TET. An MTB decision to deliver PORT was made for 117 patients (43%). PORT was ultimately initiated in 101 patients. The most frequent reason for not delivering PORT was excessive (>3 months) delay after surgery. Dose-volume constraints defined by the International Thymic Malignancy Interest Group were followed in all but four patients., Conclusion: Our data provide a unique insight into the decision-making process for PORT in TETs, highlighting the need for systematic discussion at an expert MTB, while stressing the value of current available guidelines., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Earlier studies indicated that bevacizumab could favorably be combined with radiation. However excessive damage to tumor vasculature can result in radioresistance and clinical data suggest that treatment sequencing may be important when combining bevacizumab with radiation. The aim of this study was to evaluate whether αvβ3 scintigraphic imaging could provide information to determine the optimal combination schedule of bevacizumab and radiotherapy on a lung adenocarcinoma model in mice., Methods: The tumor volume and angiogenesis changes induced after bevacizumab and radiation treatment were evaluated using (99m)Tc-RGD on a microSPECT/CT. First, we determined the optimal dose regimen for bevacizumab and radiotherapy alone. Second, the combined effects of bevacizumab and radiation were evaluated according to the combination timing (radiation 2, 24, 48 hours after bevacizumab and 48 hours before bevacizumab)., Results: The optimal dose regimen is 20mg/kg for bevacizumab and 12.5 Gy for radiotherapy with a significant decrease of tumoral uptake and volume at day 9 compared to the controls (+8.8%, +7.7%, and +44% volume, respectively, and +9.8%, +3.8%, and +207% uptake, respectively). Scintigraphic imaging showed a significant increased RGD tumor uptake two hours after bevacizumab treatment compared to 24 hours and controls (p=0.02). When bevacizumab treatment was combined with radiation, the best combination appears to be the administration of bevacizumab two hours prior to radiation with better results than single treatments (p < 0.05). On the contrary, bevacizumab given 24 hours prior to radiation led to less tumor growth delay compared to a single agent, without significant difference compared to the controls. Histological results confirmed these data with an increased percentage of necrosis (p=0.04) and a decrease of angiogenesis (p=0.04) in the optimal combination group., Conclusions: The RGD tracer helps us identify the vascular normalization window and it shows a supra-additive effect of bevacizumab when administered two hours before radiotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Large doses per fraction are not recommended in daily radiotherapy due to a higher risk of late normal tissue injury. The technical refinements of modern radiotherapy and suggestions that some tumors could be sensitive to dose per fraction have renewed the interest in hypofractionated schedules. The estimation of α/β ratio value requires large samples of carefully evaluated patients in whom total and fractional doses have varied independently. Tumor repopulation has to be considered when the treatment duration is altered. Without setting aside conflicting publication, the α/β ratio values for prostate and breast (after lumpectomy) cancers could be as low as 2.5 Gy and 4 Gy, respectively. While it is too early to change our routine protocols, the time has come to conduct clinical trials comparing different fractionation schedules., (Copyright © 2013. Published by Elsevier SAS.)

Objectives: A national survey was conducted among the radiation oncology residents about their clinical activities and responsibilities. The aim was to evaluate the clinical workload and to assess how medical tasks are delegated and supervised., Materials and Methods: A first questionnaire was administered to radiation oncology residents during a national course. A second questionnaire was mailed to 59 heads of departments., Results: The response rate was 62% for radiation oncology residents (99 questionnaires) and 51% for heads of department (30). Eighteen heads of department (64%) declared having written specifications describing the residents' clinical tasks and roles, while only 31 radiation oncology residents (34%) knew about such a document (P=0.009). A majority of residents were satisfied with the amount of medical tasks that were delegated to them. Older residents complained about insufficient exposure to new patient's consultation, treatment planning and portal images validation. The variations observed between departments may induce heterogeneous trainings and should be addressed specifically., Conclusion: National specifications are necessary to reduce heterogeneities in training, and to insure that the residents' training covers all the professional skills required to practice radiation oncology. A frame endorsed by academic and professional societies would also clarify the responsibilities of both residents and seniors., (Copyright © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The dense lymphatic network of the esophagus facilitates tumour spreading along the cephalo-caudal axis and to locoregional lymph nodes. A better understanding of microscopic invasion by tumour cells, based on histological analysis of surgical specimens and analysis of recurrence sites, has justified a reduction in radiotherapy target volumes. The delineation of the clinical target volume (CTV) depends on tumour characteristics (site, histology) and on its spread as assessed on endoscopic ultrasonography and ((18)F)-fluorodeoxyglucose positron-emission tomography (FDG-PET). We propose that positive and negative predictive values for FDG-PET should be used to adapt the CTV according to the risk of nodal involvement., (Copyright © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Acute radiation-induced esophagitis includes all clinical symptoms (odynophagia, dysphagia) occurring within 90 days after thoracic irradiation start. Its severity can be graded using RTOG and CTCAE scales. The clinical risk factors are: age, female gender, initial performance status, pre-therapeutic body mass index, pre-therapeutic dysphagia, tumoral and nodal stage, delivered dose, accelerated hyperfractionned radiotherapy, concomitant association of chemotherapy to radiotherapy and response to the treatment. The dosimetric parameters predictive of esophagitis are: mean dose, V(20Gy), V(30Gy), V(40Gy), V(45Gy) and V(50Gy). Amifostine is the only drug to have a proven radioprotective efficacy (evidence level C, ESMO recommendation grade III). The medical management of esophagitis associates a diet excluding irritant food, medication against gastroesophageal reflux, analgesic treatment according to the WHO scale and management of dehydration and denutrition by enteral feeding., (Copyright © 2012 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The recent advances in medical imaging have profoundly altered the radiotherapy of non-small cell lung cancers (NSCLC). A meta-analysis has confirmed the superiority of FDG PET-CT over CT for initial staging. FDG PET-CT improves the reproducibility of target volume delineation, especially close to the mediastinum or in the presence of atelectasia. Although not formally validated by a randomized trial, the reduction of the mediastinal target volume, by restricting the irradiation to FDG-avid nodes, is widely accepted. The optimal method of delineation still remains to be defined. The role of FDG PET-CT in monitoring tumor response during radiotherapy is under investigation, potentially opening the way to adapting the treatment modalities to tumor radiation sensitivity. Other tracers, such as F-miso (hypoxia), are also under clinical investigation. To avoid excessive delays, the integration of PET-CT in routine practice requires quick access to the imaging equipment, technical support (fusion and image processing) and multidisciplinary delineation of target volumes., (Copyright © 2011 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Dose escalation in prostate cancer is made possible due to technological advances and to precise dose-volume constraints to limit normal tissue damage. This article is a literature review focusing on the correlations between exposure (doses and volumes) of organs at risk (OAR) and rectal, urinary, sexual and bone toxicity, as well as on mathematical models aiming at toxicity prediction. Dose-volume constraint recommendations are presented that have been shown to be associated with reduced rectal damage. Indeed, the clinical data is relatively strong for late rectal toxicity (bleeding), with constraints put on both the volume of the rectum receiving high doses (≥70 Gy) and the volume receiving intermediate doses (40 to 60 Gy). Predictive models of rectal toxicity (Normal Tissue Complication Probability) appear to accurately estimate toxicity risks. The correlations are much weaker for the bulb and the femoral heads, and nearly do not exist for the bladder. Further prospective studies are required, ideally taking into account patient-related risk factors (co-morbidities and their specific treatments), assays of normal tissue hypersensitivity to ionizing radiation and mathematical models applied on 3D images acquired under the treatment machine (e.g. Cone Beam CT)., (Copyright © 2010. Published by Elsevier SAS.)

The a priori evaluation of normal tissue complication probability is an important issue for the radiation oncologist looking for the best therapeutic index. The advances in radiobiological and technological knowledge provide a better understanding of the determinants of radiation effects. The amount of information required to optimize the treatment modalities justifies the use of mathematical models linking the treatment characteristics (dose, volume, treatment time...) to the likelihood of complications. The radiation oncologist needs a minimal understanding of the mathematical models and their limits to justify his prescriptions., (Copyright (c) 2010 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Introduction: Cisplatin in combination with vinorelbine has reported an optimal activity/tolerance ratio when used in combination with radiotherapy in locally advanced unresectable non-small cell lung cancer. The currently available oral formulation of vinorelbine should be easier to use assuming a similar activity profile. An international phase II trial with vinorelbine oral and cisplatin as induction followed by oral vinorelbine and cisplatin with concomitant radiotherapy was implemented to evaluate the efficacy in terms of objective response (OR) following this combination as primary end point and duration or response, progression-free survival, overall survival, and safety as secondary endpoints., Material and Methods: The study included patients between 18 and 75 years, with histologically proven untreated locally advanced inoperable stage IIIA/IIIB (supraclavicular lymph nodes and pleural effusion excluded) non-small cell lung cancer, adequate bone marrow, hepatic and renal function, Karnofsky performance status >/=80%. Patients were treated with oral vinorelbine 60 mg/m day 1,8 cycle 1 and 80 mg/m day 1,8 cycle 2 (if no grade 3-4 toxicity) and cisplatin 80 mg/m day 1 every 3 weeks for 2 cycles as induction. Patients without progression received oral vinorelbine 40 mg/m day 1, 8 and cisplatin 80 mg/m day 1 every 3 weeks for 2 more cycles with radiotherapy 66 Gy in 6.5 weeks., Results: Patient and disease characteristics (n = 54) included: median age 57 years; female sex 24%; stage IIIA 48% and IIIB 52%; Squamous carcinoma 59%, Karnofsky performance status 100% (range, 80-100%) 50%, patients >/=5% weight loss at baseline 7%. Relative dose intensities of oral vinorelbine/cisplatin were 86%/93% and 97%/98% at induction and in combination with radiotherapy, respectively. Forty-one patients (76%) increased oral vinorelbine from 60 to 80 mg/m day during induction (reasons for nonescalation: hematological 7 patients, nonhematological 2 patients, error 4 patients). After two cycles of chemotherapy induction, the OR intent-to-treat in the 54 patients was 37%. Toxicities during induction were as follows: Neutropenia G3-4 (28%), Febrile Neutropenia (7%), nausea G3 (11%), vomiting G3-4 (9%), anorexia G3 (4%), diarrhea G4 (2%), constipation G3 (2%). Forty-seven out of 54 (87%) patients received concomitant chemo-radiotherapy.Median radiotherapy delivered dose was 66 Gy. Tolerance: 9% G3 Neutropenia; 4% G3 dysphagia/radiation; 2% G3 radiation dermatitis. Late pulmonary fibrosis was reported in one patient (1.8%). One month after completion of chemo-radiotherapy, the overall OR intent-to-treat in the 54 patients was 54% (95% CI: 40-67%). With a median follow-up of 37 months (95% CI: 34-41) the median progression-free survival and overall survival were: 12.5 (95% CI: 9.6-16.4) and 23.4 (95% CI: 17.6-29.8) months, respectively., Conclusion: Oral vinorelbine in combination with cisplatin is an effective combination in stage IIIA/IIIB patients. The excellent tolerance profile allowed to complete concomitant chemo-radiotherapy in 87% of patients. Oral vinorelbine in combination with cisplatin is a new and promising option that facilitates the administration of concomitant chemo-radiotherapy with high rates of treatment completion.

Introduction: Between May 2002 and May 2004, eight French comprehensive cancer centres did a prospective nonrandomized study including 200 patients, 100 with cancer of the prostate and 100 with head and neck cancers. Half of each patient group was treated by IMRT and the others by RTC 3D. This clinical study was associated with an economic study and a physics study. We report here the first results., Patients and Methods: For the clinical study, the analysis of the data of the first 88 patients irradiated for a prostatic cancer shows that 39 received RTC and 49 IMRT with a mean dose of 78 Gy at the ICRU point at 2 Gy per fraction. For H&N tumours, the preliminary analysis was done on the 87 first patients with a mean follow-up of 11.5 months (2 to 25 months) and a median of 8.4 months for the IMRT groups and 13.2 months for the RTC group. The economic study was done on the first 157 patients included during the first 18 months: 71 treated by RTC (35 for H&N and 36 for prostate) and 86 treated by IMRT (38 for H&N and 48 for prostate). The assessment of the direct costs was realized by a micro-costing technique. The physical study compared dose distributions for both techniques and has created quality control recommendations., Results: Clinical studies of the acute reactions do not show any difference between groups, but we want to point out the short follow-up and the relatively high dose delivered to cancers of the prostate. The physics study demonstrates that IMRT is technically feasible in good clinical conditions with high quality assurance, a good reproducibility and precision. Dosimetric data show that IMRT could certainly spare organs at risk more than RTC for H&N tumours. The direct costs of "routine" treatments for H&N tumours were 4922 euros for IMRT versus 1899 euros for RTC and for the prostatic cancers 4911 euros for IMRT versus 2357 for RTC.

Respiration-gated radiotherapy offers a significant potential for improvement in the irradiation of tumor sites affected by respiratory motion such as lung, breast and liver tumors. An increased conformality of irradiation fields leading to decreased complications rates of organs at risk (lung, heart...) is expected. Respiratory gating is in line with the need for improved precision required by radiotherapy techniques such as 3D conformal radiotherapy or intensity modulated radiotherapy. Reduction of respiratory motion can be achieved by using either breath hold techniques or respiration synchronized gating techniques. Breathhold techniques can be achieved with active, in which airflow of the patient is temporarily blocked by a valve, or passive techniques, in which the patient voluntarily breath-hold. Synchronized gating techniques use external devices to predict the phase of the respiration cycle while the patient breaths freely. These techniques presently investigated in several medical centers worldwide. Although promising, the first results obtained in lung and liver cancer patients require confirmation. Physical, technical and physiological questions still remain to be answered. This paper describes the most frequently used gated techniques and the main published clinical reports on the use of respiration-gated radiotherapy in order to evaluate the impact of these techniques.

The aim of quality control procedures during radiation therapy is to check the consistency between actual and prescribed treatments. Given the technical complexity of modern radiotherapy, stricter policies are necessary to meet increasing requirements for quality and safety. Among the various tools available, electronic imaging systems play an increasing role in patient-beam position checking and in vivo dose measurements. Written procedures will have to be established in order to describe the control modalities and frequency, as well as the rules for error corrections according to the treatment intent. Non medical staff will be devoted to new tasks, under the radiation oncologist's responsibility. A special attention should be directed at electronic archives, since the present technology is unlikely to meet the legal requirement to keep medical records accessible for at least 30 years.

Purpose: Conformal irradiation of non-small cell lung carcinoma (NSCLC) is largely based on a precise definition of the nodal clinical target volume (CTVn). The reduction of the number of nodal stations to be irradiated would render tumor dose escalation more achievable. The aim of this work was to design an mathematical tool based on documented data, that would predict the risk of metastatic involvement for each nodal station., Methods and Material: From the large surgical series published in the literature we looked at the main pre-treatment parameters that modify the risk of nodal invasion. The probability of involvement for the 17 nodal stations described by the American Thoracic Society (ATS) was computed from all these publications and then weighted according to the French epidemiological data. Starting from the primitive location of the tumour as the main characteristic, we built a probabilistic tree for each nodal station representing the risk distribution as a function of each tumor feature. From the statistical point of view, we used the inversion of probability trees method described by Weinstein and Feinberg., Results: Taking into account all the different parameters of the pre-treatment staging relative to each level of the ATS map brings up to 20,000 different combinations. The first chosen parameters in the tree were, depending on the tumour location, the histological classification, the metastatic stage, the nodal stage weighted in function of the sensitivity and specificity of the diagnostic examination used (PET scan, CAT scan) and the tumoral stage. A software is proposed to compute a predicted probability of involvement of each nodal station for any given clinical presentation., Conclusion: To better define the CTVn in NSCLC 3DRT, we propose a software that evaluates the mediastinal nodal involvement risk from easily accessible individual pre-treatment parameters.

Most of the concepts and terms related to conformal radiotherapy were produced by English-speaking authors and eventually validated by international groups of experts, whose working language was also English. Therefore, a significant part of this literature is poorly accessible to the French-speaking radiation oncology community. The present paper gathers the 'official' definitions already published in French, along with propositions for the remaining terms which should be submitted to a more formal and representative validation process.

Conformal irradiation of brain tumours is based on the three-dimensional reconstruction of the targeted volumes and at-risk organ images, the three-dimensional calculation of the dose distribution and a treatment device (immobilisation, beam energy, collimation, etc.) adapted to the high precision required by the procedure. Each step requires an appropriate methodology and a quality insurance program. Specific difficulties in brain tumour management are related to GTV and CTV definition depending upon the histological type, the quality of the surgical resection and the medical team. Clinical studies have reported dose escalation trials, mostly in high-grade gliomas and tumours at the base of the skull. Clinical data are now providing a better knowledge of the tolerance of normal tissues. As for small tumours, the implementation of beam intensity modulation is likely to narrow the gap between conformal and stereotaxic radiotherapy.

The significantly higher human and material costs induced by the development of conformal radiotherapy cannot be ignored. In France, the present criteria for medical reimbursements underestimate the costs related to treatment preparation and evaluation, slowing down the implementation of new equipment and therapeutic practices. To fit the legitimate concerns regarding health cost containment, conformal radiotherapy should be submitted to appropriate economic analyses. These analyses are based on rigorous methods aimed at weighing the actual costs of conformal treatment by the benefits achieved in terms of tumor control, normal tissue complication and the patients' quality of life. The conclusions from the few studies published to date are rather in favour of conformal radiotherapy when compared to alternative therapeutic procedures. These early results need to be confirmed in order to support more rational reimbursement modalities to promote innovative treatments.

A comprehensive understanding of the radiobiological bases of total body irradiation (TBI) is made difficult by the large number of normal and malignant tissues that must be taken into account. In addition, tissue responses to irradiation are also sensitive to associated treatments, type of graft and a number of patient characteristics. Experimental studies have yielded a large body of data, the clinical relevance of which still requires definite validation through randomized trials. Fractionated TBI schemes are able to reduce late normal tissue toxicity, but the ultimate consequences of the fractional dose reduction do not appear to be equivocal. Thus, leukemia and lymphoma cells are probably more radiobiologically heterogeneous than previously thought, with several cell lines displaying relatively high radioresistance and repair capability patterns. The most primitive host-type hematopoietic stem cells are likely to be at least partly protected by TBI fractionation and may hamper late engraftment. Similarly, but with possibly conflicting consequences on the probability of engraftment, the persistence of a functional marrow stroma may also be fractionation-sensitive, while higher rejection rates have been reported after T-depletion grafts and fractionated TBI. In clinical practice (as for the performance of relevant clinical trials), the influence of these results are rather limited by the heavy logistic constraints created by a sophisticated and time-consuming procedure. Lastly, clinicians are now facing an increasing incidence of second cancers, at least partly induced by irradiation, which jeopardize the long-term prospects of otherwise cured patients.

The choice of dose and fractionation for total body irradiation is made difficult by the large number of considerations to be taken into account. The outcome of bone marrow transplantation after total body irradiation can be understood in terms of tumour cell killing, engraftment, and normal tissue damage, each of these endpoints being influenced by irradiation-, disease-, transplant-, and patient-related factors. Interpretation of clinical data is further hampered by the overwhelming influence of logistic constraints, the small numbers of randomised studies, and the concomitant variations in total dose and fraction size or dose rate. So far, three cautious conclusions can be drawn in order to tentatively adapt the total body irradiation schedule to clinically-relevant situations. Firstly, the organs at risk for normal tissue damage (lung, liver, lens, kidney) are protected by delivering small doses per fraction at low dose rate. This suggests that, when toxicity is at stake (e.g., in children), fractionated irradiation should be preferred, provided that interfraction intervals are long enough. Secondly, fractionated irradiation should be avoided in case of T-cell depleted transplant, given the high risk of graft rejection in this setting. An alternative would be to increase total (or fractional) dose of fractionated total body irradiation, but this approach is likely to induce more normal tissue toxicity. Thirdly, clinical data have shown higher relapse rates in chronic myeloid leukaemia after fractionated or low dose rate total body irradiation, suggesting that fractionated irradiation should not be recommended, unless total (or fractional) dose is increased. Total body irradiation-containing regimens, primarily cyclophosphamide/total body irradiation, are either equivalent to or better than the chemotherapy-only regimens, primarily busulfan/cyclophosphamide. Busulfan/cyclophosphamide certainly represents a reasonable alternative, especially in patients who may not be eligible for total body irradiation because of prior irradiation to critical organs.

The daily practice of radiation oncology is increasingly influenced by the late tolerance of normal tissues. The treatment decision must be based on detailed arguments and the physician's duty to extensively inform his patients is emphasised every day. The incidence and severity of radiation-induced sequelae and late complications can be reduced by decreasing the total dose to the normal tissues, and by decreasing the dose protraction, provided that the interval between fractions remains longer than 6 to 8 hours. This approach yields a selective protection of late responding normal tissues, since tumours are less sensitive to the effects of fractionation. Despite its own limitations, the linear- quadratic model is nowadays the standard method to compare the biological effects of different radiation treatments.

Purpose: Analysis of the preliminary results of a phase I study investigating the feasibility of concomitant chemotherapy with daily doses of carboplatin (20 to 25 mg/m2/d over 45 or 10 min) and accelerated chest irradiation (60 to 64 Gy over 4 weeks, 2 Gy per fraction, using the concomitant boost technique)., Materials and Methods: This combination was given alone or following three cycles of induction chemotherapy (cisplatin, 25 mg/m2 per day from d1 to d5; 5-fluorouracil, 600 mg/m2 per day from d1 to d5 and vinorelbine, 25 mg/m2 per day at d1 and d5 with a 4-week interval) in 15 patients with locally advanced unresectable non-small cell lung cancer. All patients received the planned sequence., Results: The dose-limiting toxicity was esophagitis (5 out of 15 grade 4). No toxic deaths were observed. The tumor response rate was high: six out of 15 complete responses and 14 out of 15 tumor regressions greater than 50%. The median survival was not reached after a mean follow-up of 14 months (range, 6-28 months)., Conclusion: We are now planning a multicenter phase II study using the following combination: 20 mg/m2 of daily carboplatin over 10 min and a 60-Gy irradiation dose over 4 weeks.

The potential tailoring of radiotherapy modalities to the biological characteristics of individual tumours and normal tissues appears to be an exciting way to improve the therapeutic, ratio in radiation therapy patients. Numerous assays have been proposed to provide the clinician with the biological information necessary to predict the outcome after irradiation and to guide the treatment prescription, but none of them has made its way to daily practice. Major difficulties are due to the technical burden of the procedures, the poor characterization of the assayed cells, and, moreover, the high complexity of tumour and normal tissues biology. The present paper reviews the present status of the assessment of tumour cells radiosensitivity, proliferation and oxygenation. Research remains extremely active in the field of biological predictors of response to irradiation. Future steps forwards are expected from progress in the available technologies, (re-)discovery of apoptosis and investigation of normal tissue tolerance.

Late damages to the skin and subcutaneous tissues are almost inescapable because of the high skin doses required in the irradiation of breast tumours. While the clinical and histological descriptions date back to the first decades of the therapeutic use of ionising radiation, the recent advances in cellular and molecular biology have significantly contributed to the increased understanding of late skin injury mechanisms. In particular, sub-cutaneous fibrosis appears to be the partly reversible results of a continuous and self-maintained local process, possibly sensitive to therapeutic intervention. A second very active research avenue is the development of biologic assays potentially able to predict the probability of increased normal tissue injury after irradiation in individual patients. Such a test would allow the adaptation of the treatment modalities to the radiobiological behaviour of normal tissues. To date, these expectations have not been met. The quality of the irradiation and its modalities (total dose, fractionation, inter fraction interval) remain the main ways to achieve an optimal functional and cosmetic outcome.

Cutaneous radiation-induced fibrosis (RIF) is characterized by a skin retraction or atrophy, toughness to the palpation and often entails functional limitation. Its clinical evaluation remains poorly quantified. The aim of this study was to propose an analytical method to quantify RIF skin surface with the replica technique. In this preliminary study, we report the qualitative and quantitative evaluation of the cutaneous microrelief in 44 healthy controls and in four patients presenting a superficial RIF, 3 to 20 years after radiotherapy for cancer. The microrelief of these RIF presented an abnormal anisotropy with a parallel reorganization of cutaneous valleys in three cases out of four, suggesting a premature radiation-induced ageing of the skin. Each subject being his own control, the relative vertical amplitude of the skin microrelief was +/-15% in control skin. Vertical amplitude was respectively increased by 84% in one inflammatory fibrosis (3 years after RT), decreased by 18% in one evolutive fibrosis (6 years after RT), decreased by 26% in one voluminous stabilized fibrosis (8 years after RT) and decreased by 53% in one atrophic fibrosis (20 years after RT). The present study suggests that the variations of the microrelief parameters could reflect the RIF evolution. This technique requires a validation in a larger series of patients, including patients with telangiectasia.

Recent studies have shown that experimental tumors could be treated more efficiently with ionizing radiation if genetic material was transfered into tumor cells. Several approaches have been reported, and among them, the first one consisted of increasing the apoptotic response to radiation by modulating genes involved in the regulation of the apoptotic pathway. Indeed the modulation of p53 and bcl-2 gene expression has recently been used successfully in several experimental models to increase the apoptotic death after radiation. A second approach consisted of taking advantage of the conditional expression of some genes after exposure to ionizing radiation. Indeed, some genes exhibit a radio-inducible promoter which can be combined to a gene, able to enhance or decrease the biological effect of radiation. The irradiation of such a transgene under the control of a radio-inducible promoter can lead to a second biological effect, concomitant to the irradiation, as reported for the TNF alpha under the control of the EGR (early growth response) promoter. A third approach consisted of enhancing the effect of radiation induced tumor cell death by the expression of a suicide gene in these cells, as suggested recently for the HSV-tk (herpes virus thymidine kinase gene). These preliminary results obtained in experimental models appear to be very promising and might improve the efficacy and specificity of radiation therapy in a not too distant future.

The potential doubling time (Tpot) is defined as the time necessary to double the number of proliferating tumor cells in the absence of spontaneous cell loss. Tpot is thought to be a better index of tumor proliferation than clinically observed tumour volume doubling time. The in vivo measurement of Tpot is a possible way to detect fast growing tumours which would be better controlled by accelerated radiotherapy. The published data demonstrate the feasibility and the safety of the technique. Large variations in Tpot values were observed in tumors with similar histology, indicating an accelerated proliferation rate in some tumors. There are technical difficulties related to intra-tumor heterogeneity, sample contamination by normal cells, and inter-laboratory variability, which question the biological interpretation of Tpot. Further studies are ongoing to establish whether the in vivo measurement of Tpot 1) provides information that is independent of the "classical" prognostic factors, and 2) allows the early recognition of the patients likely to benefit from accelerated treatment.

Prognosis of esophageal cancer is very poor. Five-year survival does not exceed 20% after radical surgery, the best available treatment. Unfortunately, only 40% of the patients are amenable to surgery because of poor general status and/or locoregional extension. Adjuvant treatment did not yield survival improvement. Preoperative radiotherapy (three randomized trials) or postoperative radiotherapy (one randomized trial) showed only a decrease of regional relapses, perhaps only for the nodes negative patients. Neoadjuvant chemotherapy obtains some interesting response rate (20-60%), but there has been no evidence yet for survival improvement. Recently, promising results were presented after combination of radiotherapy and chemotherapy. In this paper, we review the present status of combined treatment for esophageal cancer. Our multicentric group (OSOF) is now completing a phase II trial, that should soon form the basis for a phase III prospective study.